See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/303951608

Beneficial Effects of the Amino Acid Glycine

Article  in  Mini Reviews in Medicinal Chemistry · June 2016

DOI: 10.2174/1389557516666160609081602

CITATIONS READS
19 2,966

3 authors:

Israel Pérez-Torres Alejandra Zuñiga

Instituto Nacional de Cardiología Universidad Nacional Autónoma de México
97 PUBLICATIONS   1,344 CITATIONS    10 PUBLICATIONS   127 CITATIONS   

SEE PROFILE SEE PROFILE

Verónica Guarner
Instituto Nacional de Cardiología
137 PUBLICATIONS   1,403 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Evolutionary cardiology View project

translational projects View project

All content following this page was uploaded by Israel Pérez-Torres on 03 August 2018.

The user has requested enhancement of the downloaded file.

 Send Orders for Reprints to reprints@benthamscience.ae
Mini-Reviews in Medicinal Chemistry, 2016, 16, 000-000 1

REVIEW ARTICLE

Beneficial Effects of the Amino Acid Glycine

Israel Pérez-Torres1, Alejandra María Zúñiga-Muñoz1 and Verónica Guarner Lans2,*

Pathology1 and Physiology2 Departments, Instituto National de Cardiología “Ignacio Chavez”

Abstract: Glycine is the smallest non-essential, neutral and metabolically inert

ARTICLE HISTORY
Received: November 04, 2014
Revised: November 09, 2015
Accepted: June 06, 2016
DOI:
10.2174/13895575166661606090816
02
amino acid, with a carbon atom bound to two hydrogen atoms, and to an amino and
a carboxyl group. This amino acid is an essential substrate for the synthesis of
several biologically important biomolecules and compounds. It participates in the
synthesis of proteins, of the tripeptide glutathione and in detoxification reactions. It
has a broad spectrum of anti-inflammatory, cytoprotective and immunomodulatory
properties. To exert its actions, glycine binds to different receptors. The GlyR anion
channel is the most studied receptor for glycine. However, there are GlyR-
independent mechanisms for glycine cytoprotection and other possible binding V.G. Lans
molecules of glycine are the NMDA receptor and receptors GlyT1 and GlyT2.
Although, in humans, the normal serum level of glycine is approximately 300 µM, increasing glycine
intake can lead to blood levels of more than 900 µM that increase its benefic actions without having
harmful side effects. The herbal pesticide glyphosate might disrupt glycine homeostasis. Many in vitro
studies involving different cell types have demonstrated beneficial effects of the addition of glycine.
Glycine also improved conditions of isolated perfused or stored organs. In vivo studies in experimental
animals have also tested glycine as a protector molecule and some studies on the beneficial effects of
glycine after its clinical application have been done. Although at high-doses, glycine may cause toxic
effects, further studies are needed to investigate the safe range of usage of this aminoacid and to test the
diverse routes of administration.

Keywords: Anti-inflammatory, antioxidant effects, cardiovascular effects, glycine ligands, glycine, metabolic effects.

1. GLYCINE structural collagen, in which one of every 3-4 amino acids is

Glycine is the smallest non-essential, neutral and
metabolically inert amino acid, with a carbon atom bound to
two hydrogen atoms, and to an amino and a carboxyl group.
It was first proposed as a neurotransmitter in the mammalian
spinal cord in 1965. Glycine is readily synthesized by the
serine hydroxymethyl transferase enzyme from serine and it
can also be synthesized endogenously [1]. Under normal
conditions the human serum glycine concentration ranges
between 200-400µM [2].
This amino acid is an essential substrate for the synthesis
of several biologically important biomolecules and compounds
including glucose, creatinine, porphyrin and purine nucleotides,
neurotransmitters and it is also a component of bile acids and
glycocholic acid. It participates in the synthesis of proteins,
of the tripeptide glutathione and in detoxification reactions
[3]. The concentration of glycine is particularly high in
*Address correspondence to this author at the Physiology Departments,
Instituto National de Cardiología “Ignacio Chavez”, Juan Badiano 1,
Colonia Sección XVI Delegación Tlalpan, CP 14080, Mexico;
Tel: 55732911, Ext. 1362; E-mail: gualanv@yahoo.com
glycine [4]. It has a broad spectrum of anti-inflammatory,
cytoprotective and immunomodulatory properties. Glycine
significantly reduces the lipopolysaccharide (LPS)-induced
production of O2- and of tumor necrosis factor alpha (TNF-α)
[5]. Several mechanisms have been implicated in the
cytoprotective effects of glycine which include stimulation
of glutathione synthesis [6].
Although, in humans, the normal serum level of glycine
is approximately 300 µM, elevating its intake can lead to
blood levels of more than 900 µM [7] that increase its
benefic actions without having harmful side effects. In
clinical trials, up to 90g of glycine per day have been used
over several weeks without serious adverse side effects [7].
Glycine is taken up by cells via a variety of transporters,
typically by those having secondary active transport
functions coupled to uptake of hydrogen, sodium and/or
chloride ions (Cl-). In contrast, glycine insufficiency is
manifested through increased urinary excretion of
5-oxoproline and an elevation in the excretion of this product
has been observed in patients with sepsis [8]. The increase in
the excretion of this product is in accordance to the severity

1389-5575/16 $58.00+.00 © 2016 Bentham Science Publishers

2 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 Pérez-Torres et al.

of the condition. Plasma glycine concentrations fall in
volunteers infected with sandfly fever, and a decreased
concentrations of glycine, serine and cysteine were observed
in patients suffering from severe trauma [9].
Many in vitro studies involving culture of different cells
types have demonstrated beneficial effects of the addition of
glycine. These studies are summarized in Table 1. Studies on
isolated perfused or stored organs have also reported
improved conditions after glycine treatment as shown in
Table 2. In vivo studies in experimental animals have also
tested glycine as a protector molecule and the results of such
studies are summarized in Table 3. Finally some studies on
the beneficial effects of glycine after its clinical application
are shown in Table 4. The reported beneficial effects of
glycine are discussed in the present review.

Table 1. In vitro studies.

Primary cells and cells lines Concentration Effect

Protects from cell injury against tert-butylhydroperoxide, decreases tubular release of lactate
1mM or 2mM
dehydrogenase [10-13]

Renal proximal tubules 0.8mM Diminishes injury from hypoxia and hypoxia-reoxygenation [14-16]

0.25-2mM Protect against ischemia [10, 17, 18]

Protects against energy depletion by inhibitors of oxidative phosphorylation and/or glycolytic

0.4mM
energy production such as cyanide, antimycin A, NO or iodoacetate [19, 20]

Protects from hypoxia and/or hypoxia-reoxygenation injury and injury due to pH restoration from
0.2 and 0.4mM 6.2 to 7.4 [21, 22]

Hepatocytes Prevents from cold ischemic injury and injury due to warm reoxygenation [23]

Protects from cellular injury that is independent of glutathione synthesis in hepatocytes exposed to
3mM
cold ischemia [24]

2-10mM Protects cells and non-specifically blocks influx of different ions (sodium, cobalt, nickel) [25, 26]

200µM Diminishes the activation of the Kupffer cells by action of lipopolysaccharide [27]
Kupffer cells
Blunts LPS-induced calcium influx and increases Cl- intake [28]
0.1-1mM
Lymphocytes Inhibits proliferation and blunts concanavalin A induced calcium fluxes [29]

Alveolar macrophages 10µM Blunts calcium influx, increases Cl- intake and decreases superoxide and TNFα secretion [5]

Neutrophils 0.3mM

Splenic macrophages 0.55mM Inhibibits the activation of neutrophils [30], splenic macrophages [31] and CD4 lymphocytes [32]

CD4 T lymphocytes

CPA cells (bovine endothelial 1mM

Prevents the VEGF-induced cellular calcium influxes [33]
cell line)

Human umbilical vein

endothelial cells
Protects against chemical energy depletion in endothelial cells of human umbilical vein [34],
Kidney endothelial cells kidney endothelial cells [35] and PC-12 cells [36]

PC-12 cells 0.3mM

Protects against chemical energy depletion.

Liver sinusoidal endothelial
Prevents injury induced by the combined effects of stimulated ischemia-reperfusion and pH
cells
restoration [37]

Rat cortical neuron cultures 1000-2000µM Decreases hypoxic injury in neurons (DIV4-20) [38]

Blocks injury induced by re-energization and pH normalization following induced ischemia and
HL-1 cardiac myocytes 3mM
increases cell viability [39]

Protects against tert-butylhydroperoxide injury only when previous incubation with glycine is done
Human intestinal epithelial cell 1 or 5mmol 1-1
for 24 hours [40]
Beneficial Effects of the Amino Acid Glycine Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 3

Table 2. Isolated perfused or stored organs.

Organ Concentration Effect

Prevents liver injury due to perfusion first of a hypoxic and then an oxygenated buffered salt
3,6 and 12mM solution [41]
Isolated liver
Decreases liver injury induced by tert-butylhydroperoxide [42]

Upon reperfusion it minimizes injury following a period of low-flow ischemia [43]

2mM Protects heart function and viability in an experimental LPS-induced decrease of cardiac function.
Isolated heart
Attenuates the hypoxia-induced calcium influx [44]

Langendorff-perfused heart Prevents from injury associated with pH normalization upon reperfusion following ischemia [39]
10mM Decreases injury of the transplanted liver and increases survival of the recipients [45]
Cold-stored liver Decreases hepatocellular injury but without having a protective effect on bile formation [46]

Prevents from Non-parenchymal cell injury [47]

Cold-stored Kidney Improves kidney function following transplantation [48]

Ex vivo lung perfusion model 5mM Ameliorates lung injury upon warm reperfusion [49]

In situ small intestine

Decreases intestinal injury [50]
reperfusion model

Cold-stored Lung 50mM Decreases injury of the transplanted lung [51]

Table 3. In vivo studies.

Organ Concentration Effect

5-200mg·kg-1 Decreases ischemia-reperfusion injury (i.v. infusion) [52]

Decreases injury of the transplanted liver and increases survival of the recipient (iv. infusion to the
130mg·kg-1 donor) [53]
Liver
Attenuates inflammatory response for mechanical manipulation [54]

Decreases mortality, liver necrosis, lung damage and serum tumor necrosis factor after LPS
5% for 3 days
intravenous injection [55]

In metabolic syndrome animals it increases arachidonic acid concentration and GlyRβ expression, it
decreases systolic blood pressure, concentration of triglycerides and insulin in plasma, HOMA
index, albuminuria and creatinine clearance, percentage of COX pathway inhibition, concentration
1% for 8 weeks of PGE2 and TXB2 in kidney perfusate, the expression of PLA2 COX-1 and COX-2 in kidney
homogenate.
In histopathologic studies of the kidney it decreases endothelial edema, thickened glomerular basal
Kidney membrane irregulary and area of obliteration [56]

Decreases ischemia-reperfusion injury and improves renal function (higher GFR and lower plasma
5% for 2 weeks combined creatinine) [57]
with 100mg·kg-1 bolus Decreases renal vascular resistance, leading to an increase in renal plasma flow and hence in GFR.
It also decreases proximal tubular reabsorption under physiological conditions [58]

60mg·kg-1 Improves survival (recipient) and post-transplant renal function [59]

4g/kg Decreases ischemia injury and improves survival following reperfusion [60]

0.5, 0.75, 1g·kg (iv) and

Attenuates ischemia-reperfusion injury [61-64]
Small Intestine 1.5g/kg (ia)

Diminishes ischemia-reperfusion injury

5, 10, 20 or 75 mg·kg-1
In these experiments, pre-ischemic blood plasma glycine was 280, 330, 340, 380 and 680µM [65]
4 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 Pérez-Torres et al.

(Table 3) Contd….

Organ Concentration Effect

Attenuates ischemia-reperfusion injury and inflammatory response from mechanical manipulation

1g·kg-1
during the transplant [66]

Skeletal muscle 750mg·kg-1 Preserves muscle function, decrease edema and necrotic injury [67]

Lung 3.75 g Effectively improves graft function following transplantation (iv. infusion) [51]

Improves early post-ischemic right ventricular compliance and decreases myocardial injury (iv.
Heart 136mg·kg-1
infusion) [68]

Hemorrhagic shock 5% fed for 4 days Increases survival and decreases injury of lung, kidney and liver [69]

Table 4. Clinical application.

Application Dose Effect

Neurologic therapy Ameliorates cognitive deficits, dementia and increases antipsychotic treatment of schizophrenia
0.8g·kg-1·day
[70-72]

Liver transplantation Decreases injury in the transplanted liver

2mM Decreases postoperative transaminase elevations and the occurrence of bile duct strictures.
None of the patients in the glycine group required retransplantation [73]

Acute ischemic Sublingual treatment improved clinical (functional) outcome and tended to decrease the 30 day
0.5, 1or 2g·5 days
stroke mortality [74]

Glycine is oxidatively degraded to CO2, NH4+, NADH
and a methylene group by the mitochondrial glycine
cleavage system which is NAD+-dependent. The methylene
group is then accepted by tetrahydrofolate, thus forming N5,
N10-methylenetetrahydrofolate [21]. The reactions catalyzed
by the glycine cleavage system and by serine hydroxymethyl
transferase are reversible and thus can also be used for the
synthesis of glycine. Furthermore glycine is also formed
from glyoxylate aminotranferase [75].
The pervasive herbicide, glyphosate, may be disrupting
glycine homeostasis. Glyphosate is the most-used herbicide
in the world. It suppresses the synthesis of pyrrole, needed
for chlorophyll, heme and corrin [76]. It does so by acting as
a glycine mimetic in the first step of the reaction that
produces pyrrole, interfering with aminolevulinic acid
dehydratase activity [77]. The World Health Organization
recently relabeled it as “probably carcinogenic”. The human
population is currently facing a health care crisis due to the
rising incidence of multiple chronic conditions such as
diabetes, obesity, and gut dysbiosis which might be caused
in part by the consumption of glyphosate [78]. Although
evidence is accumulating that suggests that glyphosate might
be acting as a disruptive ligand in glycine receptors or as a
disruptor of enzymes that metabolize glycine, further
research is needed to verify this aspect of glyphosate's
toxicity [79]. Many of the functions of glycine make sense
in the context of glyphosate's known toxicology profile and
therefore, the excessive use of this compound may be the
reason why excessive supplementation of glycine is
warranted [76-79].
At high-doses, glycine may cause toxic effects. The
absorption of 1.5% glycine was associated with a
progressive increase in bradycardia and death when an
intravenous infusion of irrigating fluid was given to mice or
rabbits [80]. Toxicity was also observed during transurethral
resection of the human prostate and endometrial resection
[80-81]. Further studies are needed to investigate the safe
range of usage of this aminoacid that may improve disease
conditions and to test the diverse routes for its
administration.
2. RECEPTORS OF GLYCINE
To exert its actions, glycine binds to different receptors.
The glycine receptor anion channel (GlyR) is the most
studied; however, there is evidence of GlyR-independent
mechanisms for glycine cytoprotection in different tissues
[82]. Other possible receptors of glycine are N-methyl-D-
aspartate receptor (NMDA) receptor and type 1 and 2
glycine transporters (GlyT1 and GlyT2).
2.1. Glycine Receptor
Glycine binds to GlyR, which is a Cl- selective channel
or pore embedded in the cellular membrane. This receptor is
a pentameric anion channel generally consisting of four α
and one β subunits. Its α3, α4 and β the subunits interact with
gephyrin to anchor it to the membrane [35]. Activation of
this glycine-gated Cl- channel is a mechanism widely
postulated to explain the beneficial effects of glycine [31].
Beneficial Effects of the Amino Acid Glycine
The pentameric GlyR is localized in the postsynaptic
neuronal membrane of the spinal cord [83] but it is also
present in a wide variety of cells such as the renal proximal
tubular cells, hepatocytes, endothelial cells, lung, stomach
and intestinal cells [84]. GlyR was originally purified from
the rat spinal chord by affinity chromatography on amino-
strychnine-agarose columns [85] and its primary structure
was determined by complementary DNA cloning [31].
Furthermore, GlyR is also a member of the nicotinic
acetylcholine, 5-HT3, and γ-aminobutyric acid A (GABAA)
receptor family of ligand-gated ion channels which are
expressed in the central nervous system, macrophages,
leukocytes, renal cells, Kupffer cells, kidney, endothelial
cells and sperms [86].
It is formed by four α-subunits (α1-4) with about 48 kDa
and a β-subunit with about 58 kDa in weight. The α-subunit
genes are highly homologous, having a primary structure
that displays 80-90% amino acid sequence identity while the
β-subunit has a sequence similarity of 47% with the α1 -
subunit [87]. The α-subunits determine the ligand
recognition, binding and gating sites and the β subunit is
linked to cytoskeletal proteins [88]. The five subunits of
GlyR are arranged pseudo-symmetrically around a central
ion-conducting pore. This topology includes a large NH2-
terminal extracellular domain that contains disulfide bridges
of cysteine in the agonist binding site. Furthermore,
hydropathy analysis originally predicted an arrangement of
four α-helical transmembrane domains per subunit and
inclusion of a β-sheet in the transmembrane domains [89].
The functional phosphorylation sites on the α1- and β-
subunits of GlyR have been mapped to the intracellular
cysteine loop and are able to modulate its function [90].
GlyR activation depends on the presence of extracellular
Cl-. When the GlyR is activated, the resulting Cl- flux moves
the membrane potential rapidly toward the Cl- equilibrium
potential [91]. Depending on the value of the equilibrium
potential relative to the cell resting potential, the Cl- flux
may cause either a depolarization or an hyperpolarization of
the cell membrane, as well as inhibition of voltage-
dependent opening of calcium (Ca2+) channels [92]. The
opening of the glycine-sensitive anion channels causes a
rapid allosteric transition via a series of concerted molecular
motions that delay the breakage of the membrane linkages as
well as the formation of the large pores or channels in
adenosine triphosphate (ATP) depletion [35]. Indeed,
substitution of Cl- with an impermeable anion such as
gluconate prevents the inhibitory effect of glycine on
agonist-induced increases in Ca2+. In addition, influx of Cl-
could also inactivate the inositol triphosphate (IP3)-gated
Ca2+ channel and blunt release of Ca2+ from intracellular
stores [30]. The IP3-gated chloride channel on the
endoplasmatic reticulum may be inactivated when the
potential difference across the membrane is increased, thus it
is possible that influx of Cl- across the cell membrane also
increases the potential difference across the endoplasmatic
reticulum making the IP3-receptor more difficult to open
[30].
There are different isoforms of the α-subunit. Kupffer
cells express the α1-subunit while inflammatory cells contain
a different isoform; the α2-subunit. Differences in the GlyR
Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 5
subunit can lead to a different regulation. Studies have
demonstrated that long-term glycine exposure blunts
activation of alveolar macrophages and neutrophils but not
of Kupffer cells possibly suggesting the participation of the
different types of the GlyR subunit in regulation of
desensitization. Long-term dietary glycine down regulates
Cl- channel function not only in Kupffer cells but also in
neuronal tissue which depends on phosphorylation of the α-
subunit. The GlyR α3-subunit is present in Kupffer cells,
peritoneal neutrophils and in splenic and alveolar
macrophages [93]. Expression of the GlyR α4-subunit is
present in Kupffer cells, neutrophils, splenic and alveolar
macrophages but not in the spinal cord of rats [28]. Alveolar
macrophages contain a GlyR α4-subunit [5]. Furthermore, the
β-subunit mRNA was detected in Kupffer cells, splenic
macrophages, neutrophils, and alveolar macrophages
neutrophils, splenic and alveolar macrophages but no in the
spinal cord of rats [28].
GlyR are targets for number of different modulators
including ethanol, anaesthetics, picrotoxin and zinc (Zn2+).
The divalent Zn2+cation exerts a complex biphasic modulation
of α1, α2 and α1β GlyR [94]. Modulation by Zn2+ potentiates
GlyR activation at low concentrations (0-1-10 µM) and
attenuates sensitivity to glycine at higher concentrations
(<10µM) [95]. Low concentrations of Zn2+ (0.01-10µM) in
the spinal cord potentiate glycinergic currents by increasing
the apparent glycine affinity without changing the saturating
current magnitude, whereas higher concentrations (>10µM)
inhibit the current by reducing the apparent glycine affinity.
Zn2+ chelators decrease the amplitude, duration and
frequency of GlyR [96].
The alkaloid strychnine is a potent competitive inhibitor
of the GlyR acting already at 1-10µM concentrations. Apart
from strychnine, there are other antagonist which bind to the
GlyR with nanomolar affinities such as the steroid RU 5135
and 1,5-diphenyl-3,7diazaadamantan-9-ol. Inhibition of
GlyR causes convulsions, while enhancement of the glycine
receptor causes central nervous system depression and
muscle relaxation [97]. Evidence in spinal cord from GlyR
protein modification experiments indicated that the
strychnine and glycine binding sites are mutually interactive
but not identical [98]. Strychnine and its analogs are highly
selective and extremely potent competitive antagonists of
glycine with a dissociation constant of 5-10 nM [99]. In
vertebrates, strychnine poisoning abolishes glycinegic
inhibition by blocking GlyR function. The consequence is
over-excitation of the motor system resulting in muscular
convulsions [100]. Resveratrol can also inhibit GlyR without
causing convulsions [97]. Ginkgolide B, a platelet activating
factor antagonist is also a specific and potent blocker of
GlyR-gated currents in dissociated rat hippocampal
pyramidal neurons [101]. The estrogen receptor modulator
tamoxifen has recently been shown to have a particularly
dramatic potentiating effect on sub-maximal glycine
responses in cultivated spinal neurons and a 5µM
concentration caused a 6.6-fold reduction in the glycine EC50
[102].
Glyphosate may also disrupt glycine receptors, driving
Ca2+ into the tissues and opening Cl- channels [103], although
there do not appear to be any papers in the literature
6 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0
supporting this hypothesis. Strychnine interferes with GlyR
activity, and glyphosate may do so in a similar way [104].
2.2. NMDA Receptor
In addition, glycine is also a co-agonist of glutamate that
binds to NMDA. Glycine can bind to the NR1 subunit of the
NMDA receptor to potentiate its activation in the dorsal
vagal complex. This lowers the secretion of hepatic
triglyceride-rich very low-density lipoproteins by inhibiting
hepatic Scd-1 gene expression therefore contributing to
normalize hypertriglyceridemia [105]. The competitive
antagonists for the glycine-binding site in the NMDA
receptor can cause neuroprotection to different extents;
implying that the NMDA receptor may be engaged in
glycine-induced cytoprotection [35].
NMDA receptors respond to the simultaneous presence
of glutamate and glycine [106]. Studies on rats exposed to
glyphosate have shown that its mechanism of action in the
hippocampus is over-stimulation of NMDA receptors [107],
likely due to glyphosate's chelation of manganese interfering
with glutamate recycling [108] coordinated with its direct
action as a glycine mimetic.
2.3. GlyT1 and GlyT2
Other glycine transporters, known as GlyT1 and GlyT2,
which are specific and dependent on Na+ and Cl- and which
are present in the plasma membrane of the nerve terminals,
glia, pancreas, liver and retinal Muller cells have also been
described [109, 110]. GlyT1 and GlyT2 transport glycine by
a high affinity active electrogenic mechanism coupled to the
electrochemical gradient of Na+ and Cl- using a 93 kDa
subunit of the cytoplasmic anchoring protein gephyrin [85].
The GLYT system is unique among glycine transporters in
that it is highly substrate- specific and has a high affinity for
glycine. Two genes that encode for the system GLYT-like
activity have been identified, and both are members of the
Na+- and Cl- -dependent neurotransmitter transporter family,
SLC6. The gene encoding for GLYT1 is SLC6A9 and the
gene encoding for GLT2 is SLC6A5 [40]. GLYT1 is
localized predominantly at the basolateral membrane of
enterocytes and its primary function is to import glycine into
the cell, suggesting a role in meeting essential requirements
of the enterocyte, rather than in nutrient absortion [111].
Sarcosine is an endogenous amino acid that is a competitive
inhibitor of the type I glycine transporter (GlyT1), and a
NMDA receptor co-agonist [112]. Sarcosine is a breakdown
product of glyphosate, but glyphosate might itself behave
similarly to sarcosine [112]. This deserves further study.
3. EFFECT OF GLYCINE ON DYSLIPIDEMIA,
OBESITY AND METABOLIC SYNDROME
Evidence has accumulated showing that glycine protects
against a variety of diseases in experimental models of
dyslipidemia, obesity and metabolic syndrome (MS). A
study comparing 30 subjects with MS plus placebo against
30 subjects with MS plus 15/day glycine supplement for 3
months, showed that glycine can modify the activity of some
of the parameters established by NCEP/ATP III to diagnose
Pérez-Torres et al.
MS, including a decrease in blood pressure (BP) and an
increase in high density lipoprotein (HDL) [113].
Glycine supplemented to a sucrose fed rat model of MS
lowers non-esterified fatty acids (NEFAs) in plasma,
triglycerides (TG), intra-abdominal fat and BP [114].
Unpublished results from our laboratory in this same MS
model show that 1% glycine in the drinking water for a
month, decreases intra-abdominal fat which is associated
with diminished hypertrophic adiposity in MS, and with
reduced circulating TG and total fatty acids in adipocytes.
The precise mechanism by which glycine reverses adipocyte
hypertrophy remains unknown; however, there might be a
direct association between adipocyte size and amount of TG.
Reduced hypertrophy by the glycine treatment could be due
to reduced total fatty acids in adipocytes that are indicative
of the total amount of stored TG (Fig. 1). In obese C57BL-6J
mice, a scallop protein diet supplement with taurine and
glycine, prevented obesity and improved plasma lipid profile
[115].
The increase in circulating inflammatory cytokines
secreted by adipocytes in obesity such as TNF-α,
interleukins (IL)-6, interferon (IFN)-γ and IL-1B, reduces
skeletal muscle protein synthesis and increase intracellular
Ca2+ concentration triggering pathways that degrade
muscular tissue. These characteristics are also present in
mice with cancer cachexia. However, subcutaneous
injections of 1g/Kg of glycine for 21 days attenuated tumor
growth and the loss of fat mass and prevented the loss of
tumor free body mass by reducing the oxidative and
inflammatory burden and expression of genes associated
with muscle protein breakdown in cancer cachexia [116].
The treatment with 10 mM glycine decreased the mRNA
levels of IL-6, TNF-α and resistin and it increased the
mRNA levels of adiponectin in differentiated 3T3-L1
adipocites. Pretreatment with glycine for 30 min in
differentiated 3T3-L1 adipocytes before stimulation with
TNF-α, reduced the amount of active nuclear factor kappa B
(NF-κB). It is therefore possible that glycine might interfere
with the phosphorylation or ubiquitin-dependent degradation
of inhibitor of nuclear factor kB (IκBs) and that it could
accelerate the removal of the active forms of NF-κB from the
nucleus, or that a combination of these mechanisms could
take place. Glycine could be activating inhibitors of NF-κB
(IκB-α, IκB-β and IκB-ε) in differentiated 3T3-L1 adipocytes
since it suppresses TNF-α dependent NF-κB activation and,
as a result, it might decrease the expression of NF-κB-
dependent genes, such as the pro-inflammatory adipokines
TNF-α and IL-6 [117].
In obese mice generated by treatment with monosodium
glutamate (MSG/Ob) with glycine added in tap water (0.1 g/
Kg) for 60 days and compared to lean mice, glycine clearly
increased fat tissue peroxisome proliferator-activated
receptor (PPAR)-γ expression in lean but not in MSG/Ob
mice. The PPAR-γ and PPAR-α liver expression was
repressed in both groups of mice, while the expression of
PPAR-δ decreased only in lean mice. Glycine treatment also
suppressed the expression of uncoupling protein (UCP)-2,
TNF-α and IL-6 in lean mice, and increased adiponectin and
insulin serum levels. Therefore, glycine regulates the
Beneficial Effects of the Amino Acid Glycine
Fig. (1). Photomicrographs of visceral white adipose tissue of the experimental groups A (Control), B (Metabolic syndrome), C (Metabolic
syndrome plus glycine) and D (Metabolic syndrome plus glycine and strychinine. Abbreviations: N = nucleus, M = cellular membrane,
Staining. Hematoxylin-Eosin to 20x.
production of inflammatory cytokines through PPAR-γ.
These results provide clues on glycine signaling mechanisms
as an anti-inflammatory agent [118].
In addition, taurine and glycine participate in bile acid
conjugation in the liver, resulting in the formation of water-
soluble bile salts and thereby glycine can lower plasma
cholesterol level. This reduction may be the reason why
glycine may increase bile acid excretion in the fecal mass.
Glycine might decrease the methionine and choline
metabolism due to a reduced S-adenosylmethionine level in
the liver [119]. It probably stimulates the formation of
sarcosine in rats through phosphatidylcholine synthesis via
the CDP-choline pathway [120]. Furthermore, in rats fed
with cholesterol (TC)-free diet with 1.5% glycine as a
dietary supplement, a decrease of plasma TC and TG was
found.
Glycine might modify hormones and probably change the
insulin/glucagon ratio [121], which is associated with
enhanced levels of hormone-sensitive lipase in adipose tissue
and with decreased activities of hepatic lipogenic enzymes.
Changes in the insulin/glucagon ratio would lower the
synthesis and excretion of very low density lipoprotein
(VLDL) by the liver and would also modify the release of
TG from extra hepatic tissues such as adipose tissue, into
plasma via the hormone-sensitive lipase [122].
The availability of glycine during pregnancy exerts a
specific effect upon the capability of the mother to provide a
suitable nutritional environment for the development of the
cardiovascular system of her offspring. Glycine is required
for a number of critical metabolic pathways, in which it is
consumed as a fundamental building block [123].
Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 7
4. EFFECT OF GLYCINE ON INSULIN RESISTANCE
Concentrations of glycine in plasma and serum are
usually reduced in insulin resistance (IR), especially for
obese human subjects [124]. In a model of transgenic pigs
with a dominant-negative glucose-dependent insulin tropic
polypeptide receptor, which is a condition typical of type 2
diabetic human patients, the concentrations of glycine were
also decreased and significantly correlated with β-cell
dysfunction and pancreatic mass reduction [125]. Therefore,
decreased glycine in serum might be a marker for insulin
sensitivity. Although, glycine impact on adiposity and IR
could potentially be explained by improved insulin
sensitivity and/or increased antioxidant and anti-inflammatory
capacity [3]. In addition, recent results from our laboratory
show that 1% glycine in drinking water decreases insulin
concentration and HOMA-IR index. The improved insulin
sensitivity in the metabolic syndrome rats and the increased
insulin sensitivity may be associated with a decrease in
NEFAs, and to a decrease in the secretion of this hormone
[126]. However, other authors have found contradictory
results. It has been reported that ingested glycine stimulates
the secretion of insulin and that treatment with this amino
acid decreased glucose and increased insulin and
homeostatic model assessment (HOMA)-IR in muscle from
MS rats which might reflect improved IR [127]. However,
another study showed that the intravenous infusion of
glycine did not stimulate an increase in insulin concentration
[128] and furthermore, another study found that glycine and
glutamine are negatively associated with HOMA-IR in
subjects from the Framingham Heart study [129].
Glycine can stimulate glucagon release by activating the
α-cells in the pancreatic human islets acting through plasma
8 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0
membrane GlyR without stimulating insulin secretion. The
threshold of glycine to stimulate glucagon release is 0.2 mM
in plasma [130]. Studies in vivo in human subjects have
shown that oral or intravenous administration of glycine
stimulates a rise in plasma glucagon levels but not those of
insulin [128]. Another study showed that in 73 old adults
(age range, 70-85 year) glycine was the only metabolite
to reach statistical significance in association with
subcutaneous adipose tissue (SCAT), thereby identifying
glycine as a HOMA-IR associated marker of multiple
adipose-containing compartments [131].
Furthermore, glycine might prevent IR and the associated
inflammatory disease by reduced serum leptin concentration,
elevating the production of insulin and ameliorating IR
[132]. In IR obese patients there are changes in plasma
amino acid concentrations.
5. EFFECTS OF GLYCINE ON DIABETES
Many years ago, it was reported that glycine (40-50g),
given orally, resulted in a moderate reduction in blood
glucose concentrations in healthy and diabetic adults (102 to
72 mg/dL and 256 to 161 mg/dL respectively). Other studies
reported no effect on blood glucose concentration in fasting
subjects. However, intravenously administered glycine
stimulates glucagon secretion in dogs and could alter glucose
concentrations [133].
The glucose excess in type 2 diabetes alters the
functionality of the structural membrane and of transport
proteins due to non-enzymatic glycation. Oxidative glycation
induces functional alterations of endothelial cells and
stimulates monocyte-binding to the vascular endothelium
and studies have suggested that administration of glycine
prevents glycation of proteins and induces lower osmotic
damage [134]. Non-enzymatic glycation involves the
condensation reaction of the carbonyl group of sugar
aldehydes with the NH2-terminus or free-amino groups of
proteins. The initial product of this reaction is called a Schiff
base [135], which spontaneously rearranges itself into the
Amadori products. These compounds are relatively stable
intermediates that can undergo a series of complex reactions
that may lead to the formation of advanced glycation end
products (AGEs) [136]. Cataracts in the diabetic patient are
the consequence of the precipitation of non-enzymatic
glycated crystalline proteins and glycation of the retinal
vessels. Glycation causes the conformational change,
aggregation, and formation of insoluble materials. Glycine
decreased cataract genesis having a protein-antiglycating
potential effect and it acts as a glucose scavenger by self-
glycation [137]. Clinical studies have shown that glycine
lowers glycated haemoglobin (HBA) in patients with type 2
diabetes [138] and suggests that glycine may act upon TG
and insulin, slowing down their biosynthesis.
Aqueous humor in the diabetic retinopathy contains AGE
products and in streptozotocin diabetic rats 1 % w/v glycine
attenuates the percentage of opacity of the lens and
microaneurysms in the eyes [139]. In another study in
streptozotocin-induced diabetic rats, the administration of
1% of glycine in drinking water for three months ad libitum
decreased the cataracts by decreasing HBA1c. AGEs
Pérez-Torres et al.
decrease protein content, reduce the antioxidant systems
such as glutathione (GSH) and super oxide dismutase
(SOD), and decrease the activity of the polyol pathway in the
lenses [140]. In streptozotocin diabetic rats, glycine 1% in
the drinking water induced a significant decrease of TG and
inhibited non-enzymatic glycation of ocular lens proteins
[135].
In type II diabetes patients using 20g/day of glycine for 6
months, TC fractions showed a significant decrease of total
TC and HDL increase in males, without changes in low
density lipoprotein (LDL). In contrast, in females it induced
a significant decrease in LDL and elevated HDL without
changes in TC [141]. When intracellular GSH concentrations
were measured in diabetic patients, diabetic patients plus
glycine and non-diabetic control subjects a restoration of the
decreased GSH synthesis of diabetic patients was observed
when the dietary supplementation of this amino acid was
administered [142].
6. EFFECT OF GLYCINE ON THE VASCULAR
SYSTEM, HYPERTENSION AND ISCHEMIA-
REPERFUSION
Evidence has accumulated showing that glycine protects
against a variety of diseases in experimental models of
hypertension and ischemia-reperfusion. This amino acid,
when supplemented to a low protein diet of rat dams during
pregnancy, also has a beneficial effect on BP in the offspring
[123].
Glycine is required for a number of critical metabolic
pathways, such as the synthesis of the structural proteins
collagen and elastin. The perturbation of these pathways
might lead to impaired elastin formation in large blood
vessels such as the aorta, causing changes in the elastic
properties and contributing to the development of
hypertension [143]. Unpublished data from our laboratory
have shown that treatment with 1% glycine tends to increase
the amount of elastic fibers in rat aortic rings with MS (Fig. 2).
This result suggests that glycine promotes the synthesis of
elastic fibers that contribute to vasodilation associated with a
decrease in blood pressure in aortic rings in the MS rats
characterized by altered vasoreactivity.
In tumors, angiogenesis is a multistage process that
involves release of angiogenic factors from several cell types
including endothelial cells that control proliferation and
migration of other cells and synthesis of the vascular
basement membrane. Proliferation of endothelial cells is a
key step in the process by which new blood vessels grow
from established ones, and glycine may inhibit angiogenesis
by preventing endothelial cell proliferation and therefore
block the increase of tumor size. Glycine inhibits agonist-
induced increases in Ca2+, in endothelial cells by activating a
Cl- channel, and since regulation of the cell cycle is Ca2+
dependent, glycine may inhibit endothelial cell proliferation
via inhibition of Ca2+ signaling [144].
Vascular endothelial growth factor (VEGF) is one of the
key factors for the survival and proliferation of endothelial
cells. Deprivation of VEGF induces apoptosis in endothelial
cells. VEGF increases the expression of the anti-apoptotic
Beneficial Effects of the Amino Acid Glycine
Fig. (2). Effect the 1% glycine treatment in metabolic syndrome rats
in the amount of elastic fibres in the aorta. Abbreviations:
C=Control, MS=Metabolic syndrome and MS+Gly= Metabolic
syndrome plus glycine.
Bcl-2 family in human umbilical vein endothelial cells and
the over-expression of Bcl-2 prevents apoptotic cell death.
Glycine treatment causes a modest upregulation of these
anti-apototic molecules [61] that can abort the death cascade
by preventing mitochondrial damage to maintain the
integrity of the electron transport chain and promote
oxidative phosphorylation [145]. Glycine (10 mmol/L)
increases the levels of Bcl-2 protein in VEGF deprivation in
human umbilical vein endothelial cells [146]. The anti-
apoptotic effect of glycine is a unique property which might
be modulated via the GlyR. At high concentrations (near 10-
30 mM), glycine also protects lung endothelial cells against
gabexate mesilate-induced injury and the effect was not
mediated by GlyR [75].
Glycine also inhibits proliferation and migration of
smooth muscle cell [144]. Interactions between endothelial
cells, smooth muscle cells and fibroblasts play a critical role
in the regulation of angiogenesis and signaling processes that
require Ca2+ [33]. A study in rats with aortic abdominal
transplantations showed that 5% glycine treatment
minimizes histopathological changes and chronic rejection
by reducing the immune response, minimizing proliferation
and inhibiting migration of smooth muscle cells [144].
In cardiomyocyte cultures, addition of 3-10 mM glycine
during ischemia-reoxygenation prevents acute necrotic cell
death associated with pH normalization by preventing
mitochondrial permeability transition. This protective effect
of glycine delays membrane permeabilization during
hypoxia, which could reflect the opening of large anionic
channels that eventually lead to massive cell swelling and
sarcolemmal rupture [39].
7. EFFECT OF GLYCINE ON ENDOTHELIAL
NITRIC OXIDE SYNTHASE
Glycine might decrease high BP by reducing the
generation of free radicals thus increasing the availability of
nitric oxide (NO). Glycine increases NO release in aortic
ring preparations from offspring of rats with a protein
Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 9
deficient diet, and in other models of unbalanced diet, but a
change in the expression of endothelial nitric oxide synthase
(eNOS) has not been found [147].
The addition of 1% glycine to the drinking water reduces
high BP in a rat model of the MS [114]. This amino acid
may exert a protective role in the MS rat vasculature, partly
by enhancing the biosynthesis of NO that is reflected in the
normal plasma concentration of NO metabolites and in an
increase in the formation of reduced glutathione [148].
Unpublished results from our laboratory show that 1%
glycine in the drinking water for a month in a MS rat model
induced by 30% sucrose in the drinking water, decreases
hypercontractility and increases vasodilation in isolated
aortic rings. This is associated with an increase of eNOS
expression and in the ratio of the metabolites of eNOS,
nitrite and nitrate ratio (NO2-/NO3-), which is inhibited by
strychnine10µM. It has previously been described that
supplementation with glycine restores the nitrogen balance
since glycine is a vital component of the S-amino acid
metabolic pathway and it aids in the regulation of
methionine and homocysteine levels [149]. Glycine
supplementation to protein restricted animals reversed the
reduced NO levels and improved Ach and isoprenaline, a β-
adrenoreceptor agonist improving relaxation in mesenteric
arteries [147].
Excess production of NO is an important pathway in the
metabolic response to injury and inflammation and NO is a
substrate for peroxynitrite (ONOO-) formation. In cells
expressing a high-output inducible nitric oxide synthase
(iNOS), upregulation of NO synthesis occurs principally
through control of iNOS transcription. The expression of
iNOS in hepatocytes is important in the response of the liver
to oxygen reactive species (ROS). The reduction of iNOS
expression with glycine is associated with decreased
cytokine-mediated hepatic injury and decreased cytokine-
mediated hepatic dysfunction [150].
8. EFFECT OF GLYCINE ON PROSTAGLANDINS
Glycine significantly decreases the phospholipase A2
(PLA2) activation caused by hypoxia in renal tubular cells,
diminishing non-esterified arachidonic acid (AA) and
protecting against cellular damage [28]. Glycine inhibits
activation of PLA2 during hypoxia/reoxygenation and
increase membrane stability. It inhibits proteases and blocks
activation of calpains and chloride influx [151]. Glycine also
blocks the increase in free intracellular Ca2+ induced by
prostaglandin E2 (PGE2) in cultured liver parenchymal cells
from Sprague-Dawley rats [92]. In our MS model 1%
glycine treatment decreased PGE2 and TXB2 concentration
in the isolated perfused kidney [56]. Kupffer cells, isolated
from rats chronically given cyclosporin A produce more
PGE2, and this effect is blocked by glycine. PGE2 can also
modulate Cl- influx through its receptor [152]. Stimulation
with vasoactive mediators such as PGE2 or phenylephrine,
which initiate signal-transduction pathways that change the
differences in cell and endoplasmic reticulum membrane
potentials, increases the intracellular Ca2+ level in hepatic
parenchymal cells. This increase in intracellular Ca2+, caused
by PGE2 and phenylephrine, is reduced by glycine [92].
10 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 Pérez-Torres et al.

9. ANTIOXIDANT EFFECTS OF GLYCINE that increased activity of Cu/Zn-SOD induced by the

treatment with glycine could reduce the elevated oxidative
Intracellular ROS are generated by redox enzymes such
stress in our MS rat model.
as uncoupled eNOS, cytochrome p-450, NADPH oxidase,
xanthine oxidase and uncoupled mitochondrial respiration.
ROS can combine with NO to form the highly reactive
ONOO-. This specie of reactive nitrogen can spontaneously
or enzymatically be dismutated to form hydrogen peroxide
(H2O2) and molecular O2-. H2O2 can oxydize unsaturated
lipids from the cellular membrane and increase
lipoperoxidation (LPO). Glycine treatment (100 mg/kg)
decreases LPO in the liver and kidney in lead exposed rats
[153].
In addition, glycine prevents ROS formation by
minimizing the impairment of the activity of antioxidant
enzymes by inhibition of the activation of NFκB.
Furthermore, glycine is an essential component of GSH,
which consists of L-glutamate, L-cysteine and glycine and is
an important component of the antioxidant defense system
needed to protect tissues from the damaging effects of free
radicals generated as part of an inflammatory response. GSH
is needed for the detoxification processes and has indirect
effects as a radical scavenger [154]. Adequate GSH
Fig. (3). Effect of 1% glycine on Cu/Zn SOD activity in aorta of
production may be of major importance during an
inflammatory response, not only for maintaining antioxidant metabolic syndrome rats. Abbreviations: C=Control, MS=Metabolic
syndrome, C+Gly= Control plus glycine and MS+Gly= Metabolic
defenses, but also as a major intracellular source of cysteine
syndrome plus glycine.
[155]. Deficiency of GSH contributes to oxidative stress.
Glutathione peroxidases (GPx1-4) are a family of
enzymes that use GSH [156]. GPx1-4 isoforms are localized In monosodium glutamate-obese mice glycine suppresses
in all cells, and are crucial antioxidant enzymes involved in the pro-inflammatory cytokines production and increases
preventing the harmful accumulation of intracellular H2O2. adiponectin secretion in vivo through the activation PPAR-γ.
The GPx family reductively inactivates H2O2 and lipid This mechanism might help explain the effect of glycine on
hydroperoxides at the expense of GSH, which is oxidized to adipokine expression through its properties as an antioxidant
form oxidized glutathione (GSSG). Depletion of the glycine agent. Furthermore, glycine decreases the proinflammatory
concentration can decrease GSH and increase ROS. In turn, adipokines by diminishing reactive oxygen species in 3T3-
GSH concentration depletion can inhibit the GPx family L1 adipocytes and blocks activation of NF-κB. Hence, it
activity [157]. However, the inactivations of the GPx promotes down-regulation of pro-inflammatory adipokines
isoforms by depletion of GSH have not been completely [159].
elucidated. TNF-α stimulates peripheral lipolysis resulting in an
The GSH/GSSG ratio, which is the most important redox increase in NEFAs which promote the production of ROS,
couple, plays crucial roles in the antioxidant defense. It can leading to increased delivery of lipids to the liver where they
be restored by glycine when it is already decreased by are re-esterified. In an alcoholic liver disease rat model,
oxidative stress. Incubation of myelomonocytic U937 cells TNF-α mRNA was reduced dramatically by dietary glycine.
with glycine for 24h increased the concentration of GSH Glycine inhibits activation of macrophages and release of
[158]. TNF-α and attenuates LPO and GSH depletion induced by
different hepatotoxins [42]. In addition, NEFAs are
In vitro studies have demonstrated that glycine, cysteine responsible for the development of high BP, associated with
and methionine are essential for maintaining the secretory central obesity and oxidative stress and the addition of
protein production by hepatocytes. In male wistar rats that glycine to the diet reduces circulating and liver TG and
were exposed to 3g/L of lead acetate in drinking water for 5 NEFAs [160].
weeks and thereafter to glycine (100 and 500 mg/kg, orally)
once daily for 5 days or to glycine (1g/Kg, orally) once daily Aging is associated with decreased GSH, impaired
for 28 days, a decreased level of lead in bone was found. mitochondrial NEFAs oxidation and IR. These defects can
Glycine also mitigated the effects of lead on parameters be reversed with cysteine and glycine supplementation to
indicative of oxidative stress in hepatic and renal samples restore GSH [161].
and induced a significant increase in GSH levels [153]. Dietary glycine prevents hemorrhagic shock-induced
Unpublished data from our laboratory show that activation of Kupffer cells, ameliorates oxidative stress and
treatment with 1% glycine increases copper/zinc (Cu/Zn)- minimizes the impairment of the activity of antioxidant
SOD enzyme activity in aorta homogenates of MS rats (Fig. 3). enzymes manganese (Mn) Mn-SOD and Cu/Zn-SOD, GPx-1
Catalase (CAT) might also be increased. This result suggests
Beneficial Effects of the Amino Acid Glycine
and CAT which are key enzymes in the regulation of
superoxide anion release from the cell [162].
10. EFFECTS OF GLYCINE ON THE KIDNEY
Supplementation with the non-essential amino acid
glycine, in isolated rat and rabbit proximal tubules,
significantly reduces the damage caused by hypoxia; it also
inhibits protease activity, ATP depletion and cyclosporine A
nephrotoxicity [154]. In the isolated perfused kidney, glycine
diminishes the deterioration of renal function [163], and the
inhibition of sodium proximal re-absorption. In addition,
glycine induces a decrease in renal vascular resistance and a
consequent increase in glomerular filtration rate (GFR)
[164]. Glycine causes renal vasodilation and protects
cultures of proximal tubules from hypoxic injury [165]. In
isolated perfused rat kidneys, the addition of 2 mmol/L-1
glycine prevented severe morphological injury caused by
hypoxia to tubular cells in the medullary thick ascending
limb [166]. In Isolated rat and rabbit proximal tubules,
glycine strongly reduced the damage caused by various
injurious processes such as hypoxia, ouabain, metabolic
inhibitors, ionomycin and phosphate depletion [167], and
inhibits sodium reabsorption in the proximal tubule [164].
In Madin-Darby canine kidney cells with ATP depletion,
glycine acting through GlyR showed cytoprotection and it
induced extracellular signal regulated kinase (ERK)-1/2 and
serine-threonine protein kinase (AKT) in the ATP-depleted
cells. This may constitute the signaling pathways to regulate
the protective effect glycine on the permeability of the cell
membrane. Inhibition of ERK-1/2 or AKT influences cell
apoptosis under ATP depletion and glycine could inhibit
autophagy by increasing the level of phosphorylated ERK1
via ERK1/2 activation and p38 depression under ATP-
depletion [86].
The cytoprotective mechanism of glycine makes it a
potential protector against impairment of hypoxia and/or
mitochondria toxicity [86]. Glycine enables ATP-depleted
cells to maintain structural integrity despite complete
disruption of ion homeostasis. Protected by glycine, ATP-
depleted cells can sustain surprisingly high elevations of
intracellular-free Ca2+, yet survive and subsequently
proliferate. These actions may account, at least in part, for
the in vivo beneficial effects of glycine in organ
preservation, transplantation, and septic shock [168].
Glycine provided during ATP depletion completely blocked
the development of pores in the membranes. The actions of
glycine can be mimicked by cross-linking of plasma
membrane proteins with a cell-impermeant cross-linker, 3,3′-
dithiobis-sulfosuccinimidylpropionate [16].
Glycine (10 mM) restores the decrease in calpain activity
in renal proximal tubules [57]. The small subunit of calpain,
a protein participating in cell differentiation, in long-term
memory, in the regulation of cell adhesion and in signaling
pathways, contains a glycine-rich strand, which is important
for membrane association. Many physiologically important
proteins are candidate substrates for calpain, such as
cytoskeletal proteins, protein kinase C and A,
phospholipases, protein phosphatases, and the plasma
membrane Ca2+-ATPase. Therefore, activation of calpain
Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 11
during hypoxia is likely to have severe consequences for cell
function and could initiate a cascade of reactions resulting in
cell death.
Experimentally, the addition of glycine 1% to the
drinking water in a MS model showed that glycine
significantly decreases albuminuria and improves creatinine
clearance which suggests that glycine is able to protect from
renal hemodynamic changes. Glycine treatment normalized
the AA concentration and decreased the expression of the
cyclooxigenase (COX) isoforms and prostaglandins levels in
the kidney in this model [152]. Other results suggest that
glycine can modulate the expression and activity of COX
isoforms, favoring an anti-inflammatory effect and
decreasing the vasoconstriction of renal arteries, which
contributes to protect renal function and decrease BP. In
addition, dietary glycine blocks the increase in serum
creatinine and decreases glomerular filtration rates caused by
cyclosporine A. 5% glycine protects the kidney against
injury induced by brief ischemia, in part, by reducing ROS
production early after reperfusion as well as chronic hypoxia
in the outer medulla during recovery [169]. An infusion of
glycine (1mmol per 100g body weight per hour for 75
minutes) ameliorates tubular injury and renal dysfunction in
rats treated with cisplatin [170]. Glycine in the diet (5%)
shows a protective effect in vivo against renal ischemia
followed by reperfusion [169].
11. EFFECTS OF GLYCINE ON THE LIVER
All cellular proteins are potential substrates for
proteolytic enzymes and an increase in protease activity
could result in partially degraded cell structures. Inhibition
of proteases could be part of the protective effect of glycine,
since it inhibits protease activity. In recent studies, a role of
proteolytic enzymes in hypoxia-induced cell injury has been
suggested. Glycine improves the survival rate in rat liver
transplantation [2]. In livers stored in ice, glycine inhibited
metallo and aspartate protease activity [57]. Glycine inhibits
nonlysosomal Ca2+-dependent proteases and protects
hepatocytes against anoxic damage.
Glycine could protect livers in situ from reperfusion
damage by minimizing LPO and could stabilize the cell
membrane by inhibiting PLA2 leading to a reduction of AA
and eicosanoids which influence hepatic microcirculation
[7]. Hepatic injury and the subsequent repair and
inflammatory process increase fibrosis and glycine
attenuates liver fibrosis caused by carbon tetrachloride.
Attenuation of fibrosis is associated with decreased collagen
synthesis rather than increased collagen degradation [171].
Glycine inhibits activation of stellate cells and synthesis
of transforming growth factor beta (TGFβ) and these effects
can be mimicked by removal of Kupffer cells with
gadolinium chloride [171]. In liver injury induced by bile
duct ligation and vitamin D deficiency, glycine increases bile
production, it attenuates oxidative stress, apoptosis and
vitamin D deficiency [172]. Glycine supplementation (0.6
g/Kg body weight) in rats with alcohol induced
hepatotoxicity, significantly lowered the activities of serum
aspartate transaminase (AST), alanine transaminase (ALT),
12 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0
alkaline phosphatases (ALP) and γ-glutamyl transpeptidase
(GGT) and normalized the liver and brain fatty acid
composition compared with untreated alcohol-fed rats [173].
In a model of non-alcoholic steatohepatitis induced by a
diet deficient in methionine and choline, glycine
supplementation (5 g/100 g) reverted the increase in body
weight gain, elevated plasma and hepatic lipids, improved
liver function test, and restored tumor markers and the
disturbance in the expression of hepatic fatty acid transport
proteins. In rats with liver injury caused by hemorrhagic
shock, a diet including 5% of glycine protected against liver
injury and death caused by hemorrhagic shock, preventing
oxidative stress and blocking posttranslational inhibition of
antioxidant enzymes, TNF-α production, and iNOS
overexpresion [162].
Glycine reduced hepatic inflammation and necrosis in
alcoholic liver injury by inhibition of TNF-α production by
activated Kupffer cells. In these animals, total hepatic TG
production was increased by stimulated peripheral lipolysis
resulting in an increase in NEFAs, leading to increased
delivery of lipid to the liver where it was re-esterified. A
decrease in lipoprotein lipase activity by TNF-α is
responsible for decreased clearance of TG-rich lipoproteins,
such as very low density lipoproteins, leading to
hyperlipidemia [43].
The pretreatment with 5% glycine in chow for 5 days in
male wistar rats decreased tissue injury after 90% partial
hepatotectomy evidenced by decreased transaminase release,
improved histology and parameters of liver function. Glycine
pretreatments did not have adverse effects on liver
regeneration. In addition, glycine improved the hepatic
microcirculation and reduced injury in a low-flow, reflow
model in the perfused liver [32].
In another study done in Balb/c mice in which
pretreatment with glycine intraperitoneally was given 24 h
before and 1h after the intraperitoneal injection of LPS/D-
Gal showed that it protected against liver damage and that
aminotransferase levels decreased to 10% associated with
significant improvement in the degree of necrosis,
inflammation, TNF-α levels and an increase in the serum
levels of the anti-inflammatory cytokine IL-10 [26].
Cytoprotection of liver cells by glycine has been
observed in the absence of Cl- and calcium ions [174]. Other
studies showed that glycine prevents entry of sodium and the
non-physiological cations cobalt and nickel into hypoxic
hepatocytes and indicated that the protective effect of
glycine does not require the presence of Cl-. This suggests
that glycine can inhibit ion flux through nonspecific leaks
[174]. Furthermore, dietary glycine blunted the growth of
B16 melanoma tumors in mice and the development in liver
tumors caused by the nongenotoxic carcinogen and
peroxisome proliferator WY-14643 in rats [175].
12. EFFECTS OF GLYCINE ON THE INTESTINE
Glycine is a substrate for a number of membrane
transport systems in the intestine that may facilitate its
cellular uptake. GLYT1 is localized predominantly at the
basolateral membrane of enterocytes and functions primarily
Pérez-Torres et al.
to import glycine into the cell, suggesting a role in meeting
essential requirements of the enterocyte, rather than in
nutrient absorption [111].
The role of GLYT1 in the cytoprotective effect of glycine
against oxidative stress was investigated in human intestinal
epithelial cells. Glycine protected cells against the oxidative
agent ter-butyhydroperoxide and reduced the intracellular
concentrations of reactive oxygen species [40]. Orally
administred glycine competes with glucose for absorption
and stimulates the secretion, either directly or indirectly of a
glucagon-like peptide1 (GLP1) gut hormone. This hormone
potentiates or is additive with the effect of insulin in
stimulating the removal of glucose from the circulation
[136]. Glycine also inhibited the effect of glucagon on
endogenous glucose production. The effect of ingested
glycine on the postprandial glucose concentration may be
important therapeutically in persons with type 2 diabetes [3].
In the intestine, glycine protects from damage caused
during mesenteric ischemia by inhibition of apoptosis [136].
Glycine also protected against intestinal injury due to
inhibition of TNF-α in chemical models of colitis induced by
dextran sulfate sodium or trinitrobenzene sulfonic acid. Both
models involve epithelial irritation and damage prior to
activation of different immune cell populations [176].
Glycine also decreased acid secretion caused by pylorus-
ligation and protected against experimental gastric lesions
induced by hypothermic restraint stress, indomethacin and
necrotizing agents including 80% ethanol, 0.2 M sodium
hydroperoxide and 0.6 M hydrochloric acid in a dose-
dependent manner [177].
In rats with mesenteric ischemia/reperfusion injury
glycine infused at a dose of either 0.5, 0.75, or 1 mg/g
infused at the rate of 0.01 ml/g/h during the reperfusion
period showed that intestinal cell viability was preserved and
the physiologic function of small bowel was significantly
better than in the saline-treated animals [61].
13. CONCLUSIONS
Glycine protects against oxidative stress caused by a
wide variety of chemicals, drugs and toxicants at the cellular
or organ level in the liver, kidney, intestine, and vascular
system. Glycine is abundant in the diet, being a component
released during protein digestion, and is considered to be
non-toxic even in high doses. The herbal pesticide
glyphosate might alter glycine homeostasis by binding to its
receptors. Although at high-doses, glycine may cause toxic
effects, further studies are needed to investigate the safe
range that may improve disease conditions and to test the
diverse routes of its administration.
LIST OF ABBREVIATIONS
AA = Arachinonic acid
AGES = Advanced glycation end products
AKT = Serine-threonine protein kinase
ALP = Alkaline phosphatases
ALT = Alanine transaminase
Beneficial Effects of the Amino Acid Glycine Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 13

AST = Aspartate transaminase NO = Nitric oxide

2 / 3
ATP = Adenosine triphosphate NO - NO - = Nitrite and nitrate ratio
BP = Blood pressure MS = Metabolic syndrome
Ca2+ = Calcium PLA2 = Phospholipase A2
CAT = Catalase PPAR = Peroxisome proliferator-activated receptor
- alpha
Cl = Chloride ions
ROS = Species oxygen reactive
COX = Cyclooxygenase
SOD = Super oxide dismutase
eNOS = Endothelial nitric oxide synthase
TC = Cholesterol
ERK = Extracellular-signal-regulated kinase
TG = Triglycerides
GABAA = γ-aminobutyric acid
TGFB = Transforming growth factor beta
GFR = Glomerular filtration rate
TNF-α = Tumor necrosis factor alpha
GLP1 = Glucagon-like peptide1
UCP = Uncoupling protein
GlyT1 = Glycine transporter type 1
VEGF = Vascular endothelial growth factor
GlyT2 = Glycine transporter type 2
VLDL = Very low density lipoprotein
GGT = γ-glutamyl transpeptidase
Zn = Zinc
GlyR = Glycine receptor
GPx = Glutathione peroxidases CONFLICT OF INTEREST
GSH = Glutathione The author(s) confirm that this article content has no
conflict of interest.
GSSG = Oxidized glutathione
HBA = Glycated haemoglobin ACKNOWLEDGEMENTS
HDL = High density lipoprotein Declared none.
H2O2 = Hydrogen peroxide
REFERENCES
HOMA = Homeostatic model assessment [1] Roth, E. Immune and cell modulation by amino acids. Clin. Nutr.,
IFN-γ = Interferon 2007, 26 (5), 535-544.
[2] Schemmer, P.;Bradford, B.U.; Rose, M.L.; Bunzendahl, H.;
IκBs = Inhibitor of nuclear factor-κB Raleigh, J.A.; Lemasters, J.J.; Thurman, R.G. Intravenous glycine
improves survival in rat liver transplantation. Am. J. Physiol., 1999,
IL = Interleukins 276 (4 Pt 1), G924-G932.
[3] Gannon, M.C.; Nuttal, J.A.; Nuttall, F.Q. The metabolic response
iNOS = Inducible nitric oxide synthase to ingested glycine. Am. J. Clin. Nutr., 2002, 76(6), 1302-1307.
[4] González-Ortiz, M.;Medina-Santillán, R.; Martínez-Abundis, E.;
IP3 = Inositol trisphosphate von Drateln, C.R. Effect of glycine on insulin secretion and action
in healthy first-degree relatives of type 2 diabetes mellitus patients.
IR = Insulin resistance Horm. Metab. Res., 2001, 33(6), 358-360.
[5] Wheeler, M.D.; Thurman, R.G. Production of superoxide and TNF-
LDL = Low density lipoprotein alpha from alveolar macrophages is blunted by glycine. Am. J.
Physiol., 1999, 277(5 Pt 1), L952-L959.
LPO = Lipoperoxidation [6] Jackson, A.A.; Gibson, N.R.; Lu, Y.; Jahoor, F. Synthesis of
erythrocyte glutathione in healthy adults consuming the safe
LPS = Lipopolysaccharide amount off dietary protein. Am. J. Clin. Nutr., 2004, 80(1), 101-
NADH = Hydrogenated nicotinamide adenine 107.
[7] Luntz, S.P.; Unnebrink, K.; Seibert-Grafe. M.; Bunzendahl, H.;
dinucleotide Kraus, T.W.; Büchler, M.W.; Klar, E.; Schemmer, P. HEGPOL:
randomized, placebo controlled, multicenter, double-blind clinical
NAD = Nicotinamide adenine dinucleotide trial to investigate hepatoprotective effects of glycine in the
NEFAs = Non-esterified fatty acids postoperative phase of liver transplantation. BMC Surg., 2005, 17,
5-18.
NF-κB = Nuclear factor kappa B [8] Moran, B.; Persaud, C.; Jackson, A. A. Urinary excretion of 5-
oxoproline in severe inflammatory illness. Pro. Nutr. Soc., 1989,
Mn = Manganese 48, 75A.
[9] Jeevanandam, M.; Young, D. H.; Ramais, L.; Schiller, W. R.
-
ONOO = Peroxynitrite Amino aciduria of severe trauma. Am. J. Clin. Nutr., 1989, 49, 814-
822.
NMDA = N-methyl-D-aspartate receptor
14 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0
[10] Weinberg, J.M.; Davis, J.A.; Abarzua, M.; Rajan, T. Cytoprotective
effects of glycine and glutathione against hypoxic injury to renal
tubules. J. Clin. Invest., 1987, 80(5), 1446-1454.
[11] Weinberg, J.M.; Davis, J.A.; Abarzua, M.; Kiani, T. Relationship
between cell adenosine triphosphate and glutathione content and
protection by glycine against hypoxic proximal tubule cell injury.
J. Lab. Clin. Med., 1989, 113(5), 612-622.
[12] Weinberg, J.M.; Venkatachalam, M.A.; Garzo-Quintero, R.;
Roeser, N.F.; Davis, J.A. Structural requirements for protection by
small amino acids against hypoxic injury in kidney proximal
tubules. FASEB J., 1990, 4(15), 3347-3354.
[13] Weinberg, J.M.; Venkatachalam, M.A.; Goldberg, H.; Roeser,
N.F.; Davis, J.A. Modulation by Gly, Ca, and acidosis of injury-
associated unesterified fatty acid accumulation in proximal tubule
cells. Am. J. Physiol., 1995, 268(1 Pt 2) F110-F121.
[14] Mandel, L.J.; Schnellmann, R.G.; Jacobs W.R. Intracellular
glutathione in the protection from anoxic injury in renal proximal
tubules. J. Clin. Invest., 1990, 85(2), 316-324.
[15] Paller, M.S.; Patten, M. Protective effects of glutathione, glycine,
or alanine in an in vitro model of renal anoxia. J. Am. Soc.
Nephrol., 1992, 2(8), 1338-1344.
[16] Tijsen, M.J.; Peters, S.M.; Bindels, R.J.; van Os, C.H.; Wetzels,
J.F. Glycine protection against hypoxic injury in isolated rat
proximal tubules: the role of proteases. Nephrol. Dial Transplant.,
1997, 12(12), 2549-2556.
[17] Moran, J.H.; Schnellmann, R.G. Diverse cytoprotectants prevent
cell lysis and promote recovery of respiration and ion transport.
Biochem. Biophys. Res. Commun., 1997, 234(1), 275-277.
[18] Wetzels, J.F.; Wang, X.; Gengaro, P.E.; Nemenoff, R.A.; Burke,
T.J; Schrier, R.W. Glycine protection against hypoxic but not
phospholipase A2-induced injury in rat proximal tubules. Am. J.
Physiol., 1993, 264(1 Pt 2), F94-F99.
[19] Aleo, M.D.; Schnellmann, R.G. The neurotoxicants strychnine and
bicuculline protect renal proximal tubules from mitochondrial
inhibitor-induced cell death. Life Sci., 1992, 51(23), 1783-1787.
[20] Dickson, R.C.; Bronk, S.F.; Gores, G.J. Glycine cytoprotection
during lethal hepatocellular injury from adenosine triphosphate
depletion. Gastroenterology., 1992, 102(6), 2098-2107.
[21] Petrat, F.; Boengler, K.; Schulz, R.; de Groot, H. Glycine, a simple
physiological compound protecting by yet puzzling mechanism(s)
against ischaemia-reperfusion injury: current knowledge. Br. J.
Pharmacol., 2012, 165(7), 2059-2072.
[22] Qian, T.; Nieminen, A.L.; Herman, B.; Lemasters, J.J.
Mitochondrial permeability transition in pH-dependent reperfusion
injury to rat hepatocytes. Am. J. Physiol., 1997, 273(6 Pt 1),
C1783-C1792.
[23] Marsh, D.C.; Vreugdenhil, P.K.; Mack, V.E.; Belzer, F.O.;
Southard, J.H. Glycine protects hepatocytes from injury caused by
anoxia, cold ischemia and mitochondrial inhibitors, but not injury
caused by calcium ionophores or oxidative stress. Hepatology,
1993, 17(1), 91-98.
[24] Marsh, D.C.; Hjelmhaug, J.A.; Vreugdenhil, P.K.; Belzer, F.O.;
Southard, J.H. Glycine prevention of cold ischemic injury in
isolated hepatocytes. Cryobiology, 1991, 28(1), 105-109.
[25] Carini, R.; Bellomo, G.; de Cesaris, M.G.; Albano, E. Glycine
protects against hepatocyte killing by KCN or hypoxia by
preventing intracellular Na+ overload in the rat. Hepatology, 1997,
26(1), 107-112.
[26] Frank, A.; Rauen, U.; de Groot, H. Protection by glycine against
hypoxic injury of rat hepatocytes: inhibition of ion fluxes through
nonspecific leaks. J. Hepatol., 2000, 32(1), 58-66.
[27] Ikejima, K.; Qu, W.; Stachlewitz, R.F.; Thurman, R.G. Kupffer
cells contain a glycine-gated chloride channel. Am. J. Physiol.,
1997, 272(6 Pt 1), G1581-G1586.
[28] Froh, M.; Thurman, R.G.; Wheeler, M.D. Molecular evidence for a
glycine-gated chloride channel in macrophages and leukocytes.
Am. J. Physiol. Gastrointest. Liver Physiol., 2002, 283(4), 856-863.
[29] Stachlewitz, R.F.; Li, X.; Smith, S.; Bunzendahl, H.; Graves, L.M.;
Thurman, R.G. Glycine inhibits growth of T lymphocytes by an IL-
2-independent mechanism. J. Immunol., 2000, 164(1), 176-182.
[30] Wheeler, M.; Stachlewitz, R.F.; Yamashina, S.; Ikejima, K.;
Morrow, A.L.; Thurman, R.G. Glycine-gated chloride channels in
neutrophils attenuate calcium influx and superoxide production.
FASEB J., 2000, 14(3), 476-484.
Pérez-Torres et al.
[31] Li, X.; Bradford, B.U.; Wheeler, M.D.; Stimpson, S.A.; Pink,
H.M.; Brodie, T.A.; Schwab J.H.; Thurman R.G. Dietary glycine
prevents peptidoglycan polysaccharide-induced reactive arthritis in
the rat: role for glycine-gated chloride channel. Infect. Immun.,
2001, 69(9), 5883-5891.
[32] Bruck, R.; Wardi, J.; Aeed, H.; Avni, Y.; Shirin, H.; Avinoach, I.;
Shahmurov, M.; Hershkoviz, R. Glycine modulates cytokine
secretion, inhibits hepatic damage and improves survival in a
model of endotoxemia in mice. Liver Int., 2003, 23(4), 276-282.
[33] Yamashina, S.; Konno, A.; Wheeler, M.D.; Rusyn, I.; Rusyn, E.V.;
Cox, A.D.; Thurman, R.G. Endothelial cells contain a glycine-
gated chloride channel. Nutr. Cancer, 2001, 40(2), 197-204.
[34] Weinberg, J.M.; Varani, J.; Johnson, K.J.; Roeser, N.F.; Dame,
M.K.; Davis, J.A.; Venkatachalam, M.A. Protection of human
umbilical vein endothelial cells by glycine and structurally similar
amino acids against calcium and hydrogen peroxide-induced lethal
cell injury. Am. J. Pathol., 1992, 140(2) 457-471.
[35] Pan, C.; Bai, X.; Fan, L.; Ji, Y.; Li, X.; Chen, Q. Cytoprotection by
glycine against ATP-depletion-induced injury is mediated by
glycine receptor in renal cells. Biochem. J., 2005, 390(Pt2), 447-
453
[36] Zhang, K.; Weinberg, J.M.; Venkatachalam, M.A.; Dong, Z.
Glycine protection of PC-12 cells against injury by ATP-depletion.
Neurochem. Res., 2003, 28(6), 893-901.
[37] Nishimura, Y.; Romer, L.H.; Lemasters, J.J. Mitochondrial
dysfunction and cytoskeletal disruption during chemical hypoxia to
cultured rat hepatic sinusoidal endothelial cells: the pH paradox
and cytoprotection by glucose, acidotic pH, and glycine.
Hepatology, 1998, 27(4), 1039-1049.
[38] Zhao, P.; Qian, H.; Xia, Y. GABA and glycine are protective to
mature but toxic to immature rat cortical neurons under hypoxia.
Eur. J. Neurosci., 2005, 22(2), 289-300.
[39] Ruiz-Meana, M.; Pina, P.; Garcia-Dorado, D; Rodríguez-Sinovas,
A.; Barba, I.; Miró-Casas, E.; Mirabet, M.; Soler-Soler, J. Glycine
protects cardiomyocytes against lethal reoxygenation injury by
inhibiting mitochondrial permeability transition. J. Physiol., 2004,
558(Pt 3), 873-882.
[40] Howard, A.; Tahir, I.; Javed, S.; Waring, S.M.; Ford, D.; Hirst,
B.H. Glycine transporter GLYT1 is essential for glycine mediated
protection of human intestinal epithelial cells against oxidative
damage. J. Physiol., 2010, 588(Pt 6), 995-1009.
[41] Deters, M.; Strubelt, O.; Younes,M. Protection by glycine against
hypoxia-reoxygenation induced hepatic injury. Res. Commun. Mol.
Pathol. Pharmacol., 1997, 97, 199-213.
[42] Deters, M.; Siegers, C.P.; Strubelt, O. Influence of glycine on the
damage induced in isolated perfused rat liver by five hepatotoxic
agents. Toxicology, 1998, 128(1), 63-72.
[43] Zhong, Z.; Jones, S.; Thurman, R.G. Glycine minimizes
reperfusion injury in a low-flow, reflow liver perfusion model in
the rat. Am. J. Physiol., 1996, 270(2 Pt 1), G332-G338.
[44] Qi, R.B.; Zhang, J.Y.; Lu, D.X.; Wang, H.D.; Wang, H.H.; Li, C.J.
Glycine receptors contribute to cytoprotection of glycine in
myocardial cells. Chin. Med. J. (Engl)., 2007, 120(10), 915-921.
[45] den Butter, G.; Lindell, S.L.; Sumimoto, R.; Schilling, M.K.;
Southard, J.H.; Belzer, F.O. Effect of glycine in dog and rat liver
transplantation. Transplantation, 1993, 56(4), 817-822.
[46] den Butter, G.; Marsh, D.C.; Lindell, S.L.; Belzer, F.O.; Southard,
J.H. Effect of glycine on isolated, perfused rabbit livers following
48-hour preservation in University of Wisconsin solution without
glutathione. Transpl. Int., 1994, 7(3), 195-200.
[47] Currin, R.T.; Caldwell-Kenkel, J.C.; Lichtman, S.N.; Bachmann,
S.; Takei, Y.; Kawano, S.; Thurman, R.G.; Lemasters, J.J.
Protection by Carolina rinse solution, acidotic pH, and glycine
against lethal reperfusion injury to sinusoidal endothelial cells of
rat livers stored for transplantation. Transplantation, 1996, 62(11),
1549-1558.
[48] Mangino, M.J.; Murphy, M.K.; Grabau, G.G.; Anderson, C.B.
Protective effects of glycine during hypothermic renal ischemia-
reperfusion injury. Am. J. Physiol., 1991, 261(5 Pt 2), F841-F848.
[49] Omasa, M.; Fukuse, T.; Toyokuni, S.; Mizutani, Y.; Yoshida, H.;
Ikeyama, K.; Hasegawa, S.; Wada, H. Glycine ameliorates lung
reperfusion injury after cold preservation in an ex vivo rat lung
model. Transplantation, 2003, 75(5), 591-598.
Beneficial Effects of the Amino Acid Glycine
[50] Mangino, J.E.; Kotadia, B.; Mangino, M.J. Characterization of
hypothermic intestinal ischemia-reperfusion injury in dogs. Effects
of glycine. Transplantation, 1996, 62(2), 173-178.
[51] Gohrbandt, B.; Fischer, S.; Warnecke, G.; Avsar, M.; Sommer,
S.P.; Haverich, A.; Strueber, M. Glycine intravenous donor
preconditioning is superior to glycine supplementation to low-
potassium dextran flush preservation and improves graft function in
a large animal lung transplantation model after 24 hours of cold
ischemia. J. Thorac. Cardiovasc. Surg., 2006, 131(3), 724-729.
[52] Duenschede, F.; Westermann, S.; Riegler, N.; Miesner, I.; Erbes,
K.; Ewald, P.; Kircher, A.; Schaefer, H.; Schneider, J.; Schad, A.;
Dutkowski, P.; Kiemer, A.K.; Junginger, T. Different protection
mechanisms after pretreatment with glycine or alpha-lipoic acid in
a rat model of warm hepatic ischemia. Eur. Surg. Res., 2006, 38(6),
503-512.
[53] Rentsch, M.; Puellmann, K.; Sirek, S.; Iesalnieks, I.; Kienle, K.;
Mueller, T.; Bolder, U.; Geissler, E.; Jauch, K.W.; Beham, A.
Benefit of Kupffer cell modulation with glycine versus Kupffer cell
depletion after liver transplantation in the rat: effects on
postischemic reperfusion injury, apoptotic cell death graft
regeneration and survival. Transpl. Int., 2005, 18 (9), 1079-1089.
[54] Liu, Z.J.; Yan, L.N.; Li, S.W.; You, H.B.; Gong, J.P. Glycine
blunts transplantative liver ischemia-reperfusion injury by
downregulating interleukin 1 receptor associated kinase-4. Acta
Pharmacol. Sin., 2006, 27(11), 1479-1486.
[55] Ikejima, K.; Iimuro, Y.; Forman, D.T.; Thurman, R.G. A diet
containing glycine improves survival in endotoxin shock in the rat.
Am. J. Physiol., 1996, 271(1 Pt 1), G97-G103.
[56] Pérez-Torres, I.; Ibarra, B.; Soria-Castro, E.; Torrico-Lavayen, R.;
Pavón, N.; Diaz-Diaz, E.; Flores, P.; Infante, O.; Baños, G. Effect
of glycine on the cyclooxygenase pathway of the kidney
arachidonic acid metabolism in a rat model of metabolic syndrome.
Can. J. Physiol. Pharmacol., 2011, 89, 1-12.
[57] Yin, M.; Zhong, Z.; Connor, H.D.; Bunzendahl, H.; Finn, W.F.;
Rusyn, I.; Li, X.; Raleigh, J.A.; Mason, R.P.; Thurman, R.G.
Protective effect of glycine on renal injury induced by ischemia-
reperfusion in vivo. Am. J. Physiol. Renal Physiol., 2002, 282(3),
F417-F423.
[58] Thomsen, K.; Nielsen, C.B.; Flyvbjerg, A. Effects of glycine on
glomerular filtration rate and segmental tubular handling of sodium
in conscious rats. Clin. Exp. Pharmacol. Physiol., 2002, 29(5-6),
449-454.
[59] den Butter, G.; Schilling, M.K.; Lindell, S.L.; Gandolf, D.;
Southard, J.H.; Belzer, F.O. Effect of glutathione and glycine in
kidney preservation. Transplant Proc., 1993, 25(1 Pt 2), 1633- 4.
[60] Iijima, S.; Shou, .J; Naama, H.; Calvano, S.E.; Daly, J.M.
Beneficial effect of enteral glycine in intestinal
ischemia/reperfusion injury. J. Gastrointest. Surg., 1997, 1(1), 61-
67.
[61] Jacob, T.; Ascher, E.; Hingorani, A.; Kallakuri, S. Glycine prevents
the induction of apoptosis attributed to mesenteric
ischemia/reperfusion injury in a rat model. Surgery, 2003, 134(3),
457-466.
[62] Kallakuri, S.; Ascher, E.; Pagala, M.; Gade, P.; Hingorani, A.;
Scheinman, M.; Mehraein, K.; Jacob, T. Protective effect of
glycine in mesenteric ischemia and reperfusion injury in a rat
model. J. Vasc. Surg., 2003, 38(5), 1113-1120.
[63] Lee, M.A.; McCauley, R.D.; Kong, S.E.; Hall, J.C. Pretreatment
with glycine reduces the severity of warm intestinal ischemic-
reperfusion injury in the rat. Ann. Plast. Surg., 2001, 46(3), 320-
326.
[64] Lee, M.A.; McCauley, R.D.; Kong, S.E.; Hall, J.C. Influence of
glycine on intestinal ischemia-reperfusion injury. JPEN J.
Parenter. Enteral. Nutr., 2002, 26(2), 130-135.
[65] Petrat, F.; Drowatzky, J.; Boengler, K.; Finckh, B.; Schmitz, K.J.;
Schulz, R.; de Groot, H. Protection from glycine at low doses in
ischemia-reperfusion injury of the rat small intestine. Eur. Surg.
Res., 2011, 46(4), 180-187.
[66] Schaefer, N.; Tahara, K.; Schuchtrup, S.; Websky, M.V.; Overhaus,
M.; Schmidt, J.; Wirz, S.; Abu-Elmagd, K.M.; Kalff, J.C.; Hirner,
A.; Türler, A. Perioperative glycine treatment attenuates
ischemia/reperfusion injury and ameliorates smooth muscle
dysfunction in intestinal transplantation. Transplantation, 2008,
85(9), 1300-1310.
Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 15
[67] Ascher, E.; Hanson, J.N.; Cheng, W.; Hingorani, A.; Scheinman M.
Glycine preserves function and decreases necrosis in skeletal
muscle undergoing ischemia and reperfusion injury. Surgery, 2001,
129(2), 231-235.
[68] Warnecke, G.; Schulze, B.; Steinkamp, T.; Haverich, A.; Klima, U.
Glycine application and right heart function in a porcine heart
transplantation model. Transpl. Int., 2006, 19(3), 218-224.
[69] Wang, G.; Zhao, M.; Wang, E.H. Effects of glycine and
methylprednisolone on hemorrhagic shock in rats. Chin. Med. J.
(Engl)., 2004, 117(9), 13334-1341.
[70] Evins, A.E.; Fitzgerald, S.M.; Wine, L.; Rosselli, R.; Goff, D.C.
Placebo-controlled trial of glycine added to clozapine in
schizophrenia. Am. J. Psychiatry, 2000, 157(5), 826-828.
[71] Heresco-Levy, U.; Javitt, D.C.; Ermilov, M.; Mordel, C.; Horowitz,
A.; Kelly, D. Double-blind, placebo-controlled, crossover trial of
glycine adjuvant therapy for treatment-resistant schizophrenia. Br.
J. Psychiatry, 1996, 169(5), 610-617.
[72] Leung, S.; Croft, R.J.; O'Neill, B.V.; Nathan, P.J. Acute high-dose
glycine attenuates mismatch negativity (MMN) in healthy human
controls. Psychopharmacology (Berl)., 2008, 196(3), 451-460.
[73] Arora, A.S.; Nichols, J.C.; DeBernardi, M.; Steers, J.L.; Krom,
R.A.; Gores, G.J. Glycine rinse protects against liver injury during
transplantation. Transplant Proc., 1999, 31(1-2), 505-506.
[74] Gusev, E.I.; Skvortsova, V.I.; Dambinova, S.A.; Raevskiy, K.S.;
Alekseev, A.A.; Bashkatova, V.G.; Kovalenko, A.V.; Kudrin, V.S.;
Yakovleva, E.V. Neuroprotective effects of glycine for therapy of
acute ischaemic stroke. Cerebrovasc. Dis., 2000, 10(1), 49-60.
[75] Holmes, R.P.; Assimos, D.G. Glyoxylate synthesis, and its
modulation and influence on oxalate synthesis. J. Urol., 1998,
160(5), 1617-1624.
[76] Kearney, P.C.; Kaufman, D.D.; editors. Herbicides Chemistry:
Degradation and Mode of Action. CRC Press: USA, 1988.
[77] Cebeci, O.; Budak, H. Global expression patterns of three Festuca
species exposed to different doses of glyphosate using the
affymetrix genechip wheat genome array. Comp Funct Genomics,
2009, 2009, 505701.
[78] Cole, D.J. Mode of action of glyphosate - A literature analysis. In:
The herbicide glyphosate. Grossbard E.; Atkison D., Editors;
London: Butterworths, 1985, 48‐74.
[79] Zaidi, A.; Khan, M.S.; Rizvi, P.Q. Effect of herbicides on growth,
nodulation and nitrogen content of greengram. Agron Sustain Dev.,
2005, 25(4), 497-504.
[80] Baggish, M.S.; Brill, A.I.; Rosenweig, B.A.; Barbot, J.E.; Indman,
P.D. Fatal acute glycine and sorbitol toxicity during operative
hysteroscopy. J Gynecol Surg., 1993, 9(3), 137-143.
[81] Olsson, J.; Hahn, R.G. Glycine toxicity after high-dose i.v. infusion
of 1.5% glycine in the mouse. Br J Anaesth., 1999, 82(2), 250-254.
[82] Aki, T.; Egashira, N.; Yamauchi, Y.; Hama, M.; Yano, T.; Itoh, Y.;
Yamada, T.; Oishi, R. Protective effects of amino acids against
gabexate mesilate-induced cell injury in porcine aorta endothelial
cells. J. Pharmacol. Sci., 2008, 107(3), 238-245.
[83] Langosch, D.; Becker, C.M.; Betz, H. The inhibitory glycine
receptor: a ligand-gated chloride channel of the central nervous
system. Eur. J. Biochem., 1990, 194(1), 1-8.
[84] Danysz, W.; Parsons, C.G. Glycine and N-methyl-D-aspartate
receptors: physiological significance and possible therapeutic
applications. Pharmacol. Rev., 1998, 50(4), 597-664.
[85] Pfeiffer, F.; Graham, D.; Betz, H. Purification by affinity
chromatography of the glycine receptor of rat spinal cord. J. Biol.
Chem., 1982, 257(16), 9389-9393.
[86] Jiang, L.; Qin, X.; Zhong, X.; Liu, L.; Jiang, L.; Lu, Y.; Fan, L.;
He, Z.; Chen, Q. Glycine-induced cytoprotection is mediated by
ERK1/2 and AKT in renal cells with ATP depletion. Eur. J. Cell
Biol., 2011, 90(4), 333-341.
[87] Grenningloh, G.; Pribilla, I.; Prior, P.; Multhaup, G.; Beyreuther,
K.; Taleb, O.; Betz, H. Cloning and expression of the 58 kd beta
subunit of the inhibitory glycine receptor. Neuron, 1990, 4(6), 963-
970.
[88] Kuhse, J.; Laube, B.; Magalei, D.; Betz, H. Assembly of the
inhibitory glycine receptor: identification of amino acid sequence
motifs governing subunit stoichiometry. Neuron, 1993, 11(6),
1049-1056.
[89] Görne-Tschelnokow, U.; Strecker, A.; Kaduk, C.; Naumann, D.;
Hucho, F. The transmembrane domains of the nicotinic
16 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0
acetylcholine receptor contain alpha-helical and beta structures.
EMBO J., 1994, 13(2), 338-341.
[90] Swope, S.L.; Moss, S.J.; Raymond, L.A.; Huganir, R.L. Regulation
of ligand-gated ion channels by protein phosphorylation. Adv.
Second Messenger Phosphoprotein Res., 1999, 33, 49-78.
[91] Stein, V.; Nicoll, R.A. GABA generates excitement. Neuron, 2003,
37(3), 375-378.
[92] Qu, W.; Ikejima, K.; Zhong, Z.; Waalkes, M.P.; Thurman, R.G.
Glycine blocks the increase in intracellular free Ca2+ due to
vasoactive mediators in hepatic parenchymal cells. Am. J. Physiol.
Gastrointest. Liver Physiol., 2002, 283(6), G1249-G1256.
[93] Kuhse, J.; Schmieden, V.; Betz, H. Identification and functional
expression of a novel ligand binding subunit of the inhibitory
glycine receptor. J. Biol. Chem., 1990, 265(36), 22317-22320.
[94] Davies, P.A.; Wang, W.; Hales, T.G.; Kirkness, E.F. A novel class
of ligand-gated ion channel is activated by Zn2+. G. J. Biol. Chem.,
2003, 278(2), 712-717.
[95] Miller, P.S.; Beato, M.; Harvey, R.J.; Smart, T.G. Molecular
determinants of glycine receptor alphabeta subunit sensitivities to
Zn2+-mediated inhibition. J. Physiol., 2005, 566(Pt 3), 657-
670.
[96] Laube, B.; Kuhse, J.; Rundström, N.; Kirsch, J.; Schmieden, V.;
Betz, H. Modulation by zinc ions of native rat and recombinant
human inhibitory glycine receptors. J. Physiol., 1995, 483(Pt 3),
613-619.
[97] Lee, B.H.; Hwang, S.H.; Choi, S.H.; Kim, H.J.; Jung, S.W.; Kim,
H.S.; Lee, J.H.; Kim, H.C.; Rhim, H.; Nah, S.Y. Resveratrol
inhibits glycine receptor-mediated ion currents. Biol. Pharm. Bull.,
2014, 37(4), 576-580.
[98] Marvizón, J.C.; Vázquez, J.; García Calvo, M.; Mayor, F.Jr.; Ruíz
Gómez, A.; Valdivieso, F.; Benavides J. The glycine receptor:
pharmacological studies and mathematical modeling of the
allosteric interaction between the glycine-and strychnine-binding
sites. Mol. Pharmacol., 1986, 30(6), 590-597.
[99] Müller, W.E.; Snyder, S.H. Glycine high affinity uptake and
strychnine binding associated with glycine receptors in the frog
central nervous system. Brain Res., 1978, 143(3), 487-498.
[100] Dutertre, S.; Becker, C.M.; Betz, H. Inhibitory glycine receptors:
an update. J. Biol. Chem., 2012, 287(48), 40216-40223.
[101] Kondratskaya, E.L.; Fisyunov, A.I.; Chatterjee, S.S.; Krishtal, O.A.
Ginkgolide B preferentially blocks chloride channels formed by
heteromeric glycine receptors in hippocampal pyramidal neurons of
rat. Brain Res. Bull., 2004, 63(4), 309-314.
[102] Chesnoy-Marchais, D. Potentiation of glycine responses by
dideoxyforskolin and tamoxifen in rat spinal neurons. Eur. J.
Neurosci., 2003, 17(4), 681-691.
[103] Lynch, J.W. Molecular structure and function of the glycine
receptor chloride channel. Physiological Reviews., 2004, 84(4),
1051-1095.
[104] Miyakawa, N.; Uchino, S.; Yamashita, T.; Okada, H.; Nakamura,
T.; Kaminogawa, S.; Miyamoto, Y.; Hisatsune, T. A glycine
receptor antagonist, strychnine, blocked NMDA receptor activation
in the neonatal mouse neocortex. Neuroreport., 2002, 13(13),
1667-1673.
[105] Yue, J.T.; Mighiu, P.I.; Naples, M.; Adeli, K.; Lam, T.K. Glycine
normalizes hepatic triglyceride rich VLDL secretion by triggering
the CNS in high-fat fed rats. Circ. Res., 2012, 110(10), 1345-1354.
[106] Wilcox, K.S.; Fitzsimonds R.M.; Johnson, B.; Dichter, M.A.
Glycine regulation of synaptic NMDA receptors in hippocampal
neurons. J Neurophysiol., 1996, 76(5), 3415-3424.
[107] Cattani, D.; de Liz Oliveira Cavalli, V.L.; Heinz Rieg, C.E.;
Domingues, J.T.; Dal-Cim, T.; Tasca C.I.; Mena Barreto Silva,
F.R.; Zamoner, A. Mechanisms underlying the neurotoxicity
induced by glyphosate-based herbicide in immature rat
hippocampus: Involvement of glutamate excitotoxicity.
Toxicology., 2014, 320, 34-45.
[108] Samsel, A.; Seneff, S. Glyphosate, pathways to modern diseases
III: Manganese neurological diseases, and associated pathologies. .
Surgical Neurology International., 2015, 6:45.
[109] Aragón, C.; López-Corcuera, B. Structure, function and regulation
of glycine neurotransporters. Eur. J. Pharmacol., 2003, 479(1-3),
249-262.
[110] Zafra, F.; Gomeza, J.; Olivares, L.; Aragón, C.; Giménez, C.
Regional distribution and developmental variation of the glycine
Pérez-Torres et al.
transporters GLYT1 and GLYT2 in the rat CNS. Eur. J. Neurosci.,
1995, 7(6), 1342-1352.
[111] Christie, G.R.; Ford, D.; Howard, A.; Clark, M.A.; Hirst, B.H.
Glycine supply to human enterocytes mediated by high-affinity
basolateral GLYT1. Gastroenterology, 2001, 120(2), 439-448.
[112] Zhang, H.X.; Lyons-Warren, A.; Thio, L.L. The glycine transport
inhibitor sarcosine is an inhibitory glycine receptor agonist.
Neuropharmacology., 2009, 57(5-6), 551-555.
[113] Díaz-Flores, M.; Cruz, M.; Duran-Reyes, G.; Munguia-Miranda,
C.; Loza-Rodríguez, H.; Pulido-Casas, E.; Torres-Ramírez, N.;
Gaja-Rodriguez, O.; Kumate, J.; Baiza-Gutman, L.A.; Hernández-
Saavedra, D. Oral supplementation with glycine reduces oxidative
stress in patients with metabolic syndrome, improving their systolic
blood pressure. Can. J. Physiol. Pharmacol., 2013, 91(10), 855-
860.
[114] El Hafidi, M.; Pérez, I.; Zamora, J.; Soto, V.; Carvajal-Sandoval,
G.; Baños, G. Glycine intake decreases plasma free fatty acids,
adipose cell size, and BP in sucrose-fed rats. Am. J. Physiol. Regul.
Integr. Comp. Physiol., 2004, 287, R1387-R1393.
[115] Tastesen, H.S.; Keenan, A.H.; Madsen, L.; Kristiansen, K.; Liaset,
B. Scallop protein with endogenous high taurine and glycine
content prevents high-fat, high-sucrose-induced obesity and
improves plasma lipid profile in male C57BL/6J mice. Amino
Acids, 2014, 46(7), 1659-1671.
[116] Ham, D.J.; Murphy, K.T.; Chee, A.; Lynch, G.S.; Koopman, R.
Glycine administration attenuates skeletal muscle wasting in a
mouse model of cancer cachexia. Clin. Nutr., 2014, 33(3), 448-458.
[117] Blancas-Flores, G.; Alarcón-Aguilar, F.J.; García-Macedo, R.;
Almanza-Pérez, J.C.; Flores-Sáenz, J.L.; Román-Ramos, R.;
Ventura-Gallegos, J.L.; Kumate, J.; Zentella-Dehesa, A.; Cruz, M.
Glycine suppresses TNF-α-induced activation of NF-κB in
differentiated 3T3-L1 adipocytes. Eur. J. Pharmacol., 2012, 689(1-
3), 270-277.
[118] Almanza-Perez, J.C.; Alarcón-Aguilar, F.J.; Blancas-Flores, G.;
Campos-Sepulveda, A.E.; Roman-Ramos, R.; Garcia-Macedo, R.;
Cruz, M. Glycine regulates inflammatory markers modifying the
energetic balance through PPAR and UCP-2. Biomed.
Pharmacother., 2010, 64(8), 534-540.
[119] Sugiyama, K.; Ohishi, A.; Ohnuma, Y.; Muramatsu, K.
Comparison between the plasma cholesterol-lowering effects of
glycine and taurine in rats fed on high cholesterol diets. Agric. Biol.
Chem., 1989, 53(6), 1647-1652.
[120] Eloranta, T.O. Tissue distribution of S-adenosylmethionine and S-
adenosylhomocysteine in the rat. Effect of age, sex and methionine
administration on the metabolism of S-adenosylmethionine, S-
adenosylhomocysteine and polyamines. Biochem. J., 1977, 166(3),
521-529.
[121] Iritani, N.; Nagashima, K.; Fukuda, H.; Katsurada, A.; Tanaka, T.
Effects of dietary proteins on lipogenic enzymes inrat liver. J.
Nutr., 1986, 116(2), 190-197.
[122] Park, T.; Oh, J.; Lee, K. Dietary taurine or glycine supplementation
reduces plasma and liver cholesterol and triglycerides
concentrations in rats fed a cholesterol-free diet. Nutrition Res.,
1999, 19(12), 1777-1789.
[123] Jackson, A.A.; Dunn, R.L.; Marchand, M.C.; Langley-Evans, S.C.
Increased systolic blood pressure in rats induced by a maternal low-
protein diet is reversed by dietary supplementation with glycine.
Clin. Sci (Lond)., 2002, 103(6), 633-639.
[124] Newgard, C.B.; An, J.; Bain, J.R.; Muehlbauer, M.J.; Stevens,
R.D.; Lien, L.F.; Haqq, A.M.; Shah, S.H.; Arlotto, M.; Slentz, C.;
Rochon, J.; Gallup, D.; Ilkayeva, O.; Wenner, B.R.; Yancy, W.S.
Jr.; Eisenson, H.; Musante, G.; Surwit, R.S.; Millington, D.S.;
Butler, M.D.; Svetkey, L.P. A branched-chain amino acid-related
metabolic signature that differentiates obese and lean humans and
contributes to insulin resistance. Cell Metab., 2009, 9(4), 311-326.
[125] Renner, S.; Römisch-Margl, W.; Prehn, C.; Krebs, S.; Adamski, J.;
Göke, B.; Blum, H.; Suhre, K.; Roscher, A.A.; Wolf, E. Changing
metabolic signatures of amino acids and lipids during the
prediabetic period in a pig model with impaired incretin function
and reduced β-cell mass. Diabetes, 2012, 61(8), 2166-2175.
[126] Reyes López, Y.; Pérez-Torres, I.; Zúñiga-Muñoz, A.; Guarner
Lans, V.; Díaz-Díaz, E.; Soria Castro, E.; Velázquez Espejel, R.
Effect of Glycine on Adipocyte Hypertrophy in a Metabolic
Syndrome Rat Model. Current Drug Delivery., 2015, 12, in press.
Beneficial Effects of the Amino Acid Glycine
[127] Inyard, A.C.; Chong, D.G.; Klibanov, A.L.; Barrett, E.J. Muscle
contraction, but not insulin, increases microvascular blood volume
in the presence of free fatty acid-induced insulin resistance.
Diabetes, 2009, 58(11), 2457-2463.
[128] Müller, W.A.; Aoki, T.T.; Cahill, G.F. Effect of alanine and
glycine on glucagon secretion in postabsorptive and fasting obese
man. J. Clin. Endocrinol. Metab., 1975, 40(3), 418-425.
[129] Cheng, S.; Rhee, E.P.; Larson, M.G.; Lewis, G.D.; McCabe, E.L.;
Shen, D.; Palma, M.J.; Roberts, L.D.; Dejam, A.; Souza, A.L.;
Deis, A.A.; Magnusson, M.; Fox, C.S.; O'Donnell, C.J.; Vasan,
R.S.; Melander, O.; Clish, C.B.; Gerszten, R.E.; Wang, T.J.
Metabolite profiling identifies pathways associated with metabolic
risk in humans. Circulation, 2012, 125(18), 2222-2231.
[130] Li, C.; Liu, C.; Nissim, I.; Chen, J.; Chen, P.; Dolida, N.; Zhang,
T.; Nissim, I.; Daikhin, Y.; Stokes, D.; Yudkoff, M.; Bennett, M.J.;
Stanley, C.A.; Matschinsky, F.M.; Naji, A. Regulation of glucagon
secretion in normal and diabetic human islets by γ-hydroxybutyrate
and glycine. J. Biol. Chem., 2013, 288(6), 3938-3951.
[131] Lustgarten, M.S.; Price, L.L.; Phillips, E.M.; Fielding, R.A. Serum
glycine is associated with regional body fat and insulin resistance
in functionally-limited older adults. PLoS One., 2013, 8(12),
e84034.
[132] Alarcon-Aguilar, F.J.; Almanza-Perez, J.; Blancas, G.; Angeles, S.;
Garcia-Macedo, R.; Roman, R.; Cruz, M. Glycine regulates the
production of pro-inflammatory cytokines in lean and monosodium
glutamate-obese mice. Eur. J. Pharmacol., 2008, 599(1-3), 152-
158.
[133] Rocha, D.M.; Faloona, G.R.; Unger, R.H. Glucagon-stimulating
activity of 20 amino acids in dogs. J. Clin. Invest., 1972, 51(9),
2346-2351.
[134] Lezcano Meza, D.; Terán Ortíz, L.; Carvajal Sandoval, G.;
Gutiérrez de la Cadena, M.; Terán Escandón, D.; Estrada Parra, S.
Effect of glycine on the immune response of the experimentally
diabetic rats. Rev Alerg Mex., 2006, 53(6), 212-216.
[135] Alvarado-Vásquez, N.; Zamudio, P.; Cerón, E.; Vanda, B.;
Zenteno, E.; Carvajal-Sandoval, G. Effect of glycine in
streptozotocin-induced diabetic rats. Comp. Biochem. Physiol. C.
Toxicol. Pharmacol., 2003, 134(4), 521-527.
[136] Bos, D.C.; de Ranitz-Greven, W.L.; de Valk, H.W. Advanced
glycation end products, measured as skin autofluorescence and
diabetes complications: a systematic review. Diabetes Technol.
Ther., 2011, 13(7), 773-779.
[137] Ramakrishnan, S.; Sulochana, K.N. Decrease in glycation of lens
proteins by lysine and glycine by scavenging of glucose and
possible mitigation of cataractogenesis. Exp. Eye Res., 1993, 57(5),
623-628.
[138] Carvajal, S.G.; Medina, S.R.; Juárez, E.; Ramos, M.G.; Carvajal,
M.E. Effect of glycine on hemoglobin glycation in diabetic
patients. Proc. West. Pharmacol. Soc., 1999, 42, 31-42.
[139] Alvarado-Vásquez, N.; Lascurain, R.; Cerón, E.; Vanda, B.;
Carvajal-Sandoval, G.; Tapia, A.; Guevara, J.; Montaño, L.F.;
Zenteno, E. Oral glycine administration attenuates diabetic
complications in streptozotocin-induced diabetic rats. Life Sci.,
2006, 79(3), 225-232.
[140] Bahmani, F.; Bathaie, S.Z.; Aldavood, S.J.; Ghahghaei, A. Glycine
therapy inhibits the progression of cataract in streptozotocin-
induced diabetic rats. Mol. Vis., 2012, 18, 439-448.
[141] Muñoz-Carlin, M. de L.; Rodríguez-Moctezuma, J.R.; Gómez
Latorre, J.G.; Montes-Castillo, M.L.; Juárez-Adauta, S. Effects of
glycine on auditory evoked potentials among diabetic patients with
auditory pathway neuropathy. Rev. Med. Chil., 2010, 138(10),
1246-1252.
[142] Sekhar, R.V.; Mckay, S.V.; Patel, S.G.; Guthikonda, A.P.; Reddy,
V.T.; Balasubramanyam, A.; Jahoor, F. Glutathione synthesis is
diminished in patients with uncontrolled diabetes and restored by
dietary supplementation with cysteine and glycine. Diabetes Care,
2011, 34(1), 162-167.
[143] Baños, G.; Pérez-Torres, I.; El Hafidi, M. Medicinal Agents in the
Metabolic Syndrome. Cardiovasc. & Hematol. Agents in Med.
Chem., 2008, 6, 237-252.
[144] Yin, M.; Rusyn, I.; Schoonhoven, R.; Graves, L,M.; Rusyn, E.V.;
Li, X.; Li, F.; Cox, A.D.; Harding, T.W.; Bunzendahl, H.;
Swenberg, J.A.; Thurman, R.G. Inhibition of chronic rejection of
aortic allografts by dietary glycine. Transplantation, 2000, 69(5),
773-780.
Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 17
[145] Yang, J.; Liu, X.; Bhalla, K.; Kim, C.N.; Ibrado, A.M.; Cai, J.;
Peng, T.I.; Jones, D.P.; Wang, X. Revertion of apoptosis by Bcl-2:
release of cytochrome c from mitochondria blocked. Science, 1997,
275(5303), 1129-1132.
[146] Zhang, Y.; Ikejima, K.; Honda, H.; Kitamura, T.; Takei, Y.; Sato,
N. Glycine prevents apoptosis of rat sinusoidal endothelial cells
caused by deprivation of vascular endothelial growth factor.
Hepatology, 2000, 32(3), 542-546.
[147] Brawley, L.; Torrens, C.; Anthony, F.W.; Itoh, S.; Wheeler, T.;
Jackson, A.A.; Clough, G.F.; Poston, L.; Hanson, M.A. Glycine
rectifies vascular dysfunction induced by dietary protein imbalance
during pregnancy. J. Physiol., 2004, 554(Pt2), 497-504.
[148] Jackson, A.A., The glycine story. Euro. J. Clin. Nutr., 1991, 45,
59-65.
[149] Fukada, S.; Shimada, Y.; Morita, T.; Sugiyama K. Suppression of
methionine-induced hyperhomocysteinemia by glycine and serine
in rats. Biosci Biotechnol Biochem., 2006, 70(10), 2403-2409.
[150] Mikalauskas, S.; Mikalauskiene, L.; Bruns, H.; Nickkholgh, ;
Hoffmann, K.; Longerich, T.; Strupas, K.; Büchler, M.W.;
Schemmer, P. Dietary glycine protects from chemotherapy-induced
hepatotoxicity. Amino Acids, 2011, 40(4), 1139-1150.
[151] Zhong, Z.; Arteel, G.E.; Connor, H.D.; Yin, M.; Frankenberg,
M.V.; Stachlewitz, R.F.; Raleigh, J.A.; Mason, R.P.; Thurman,
R.G. Cyclosporin A increases hypoxia and free radical production
in rat kidneys: prevention by dietary glycine. Am. J. Physiol., 1998,
275(4 Pt 2), F595-F604.
[152] Soodvilai, S.; Jia, Z.; Yang, T. Hydrogen peroxide stimulates
chloride secretion in primary inner medullary collecting duct cells
via mPGES-1-derived PGE2. Am. J. Physiol. Renal Physiol., 2007,
293(5), F1571-F1576.
[153] Alcaraz-Contreras, Y.;Garza-Ocañas, L.; Carcaño-Díaz, K.;
Ramírez-Gómez, X.S. Effect of glycine on lead mobilization, lead-
induced oxidative stress, and hepatic toxicity in rats. J. Toxicol.,
2011, 2011, 430539.
[154] Bilzer, M.; Baron, A.; Schauer, R.; Steib, C.; Ebensberger, S.;
Gerbes, AL. Glutathione treatment protects the rat liver against
injury after warm ischemia and Kupffer cell activation. Digestion,
2002, 66(1), 49-57.
[155] Grimble, R.F.; Jackson, A.A.; Persaud, C.; Wride, M.J.; Delers, F.;
Engler, R. Cysteine and glycine supplementation modulate the
metabolic response to tumor necrosis factor alpha in rats fed a low
protein diet. J. Nutr., 1992, 122(11), 2066-2073.
[156] Lubos, E.; Loscalzo, J.; Handy, D.E., Glutathione peroxidase-1 in
health and disease: from molecular mechanisms to therapeutic
opportunities. Antioxid. Redox Signal., 2011, 15(7), 1957-1997.
[157] Blum, J.; Fridovich, I. Inactivation of glutathione peroxidase by
superoxide radical. Arch. Biochem. Biophys., 1985, 240(2), 500-
508.
[158] Wessner, B.; Strasser, E.M.; Spittler, A.; Roth E. Effect of single
and combined supply of glutamine, glycine, N-acetylcysteine, and
R,S-alpha-lipoic acid on glutathione content of myelomonocytic
cells. Clin. Nutr., 2003, 22(6), 515-522.
[159] Garcia-Macedo, R.; Sanchez-Muñoz, F.; Almanza-Perez, J.C.;
Duran-Reyes, G.; Alarcon-Aguilar, F.; Cruz, M. Glycine increases
mRNA adiponectin and diminishes pro-inflammatory adipokines
expression in 3T3-L1 cells. Eur. J. Pharmacol., 2008, 587(1-3),
317-321.
[160] El Hafidi, M.; Pérez, I.; Banos, G. Is glycine effective against
elevated blood pressure?. Curr. Opin. Clin. Nutr. Metab. Care,
2005, 9, 26-31.
[161] Nguyen, D.; Samson, S.L.; Reddy, V.T.; Gonzalez, E.V,; Sekhar,
R.V. Impaired mitochondrial fatty acid oxidation and insulin
resistance in aging: novel protective role of glutathione. Aging
Cell., 2013, 12(3), 415-425.
[162] Mauriz, J.L.; Matilla, B.; Culebras, J.M.; González, P,; González-
Gallego, J. , Dietary glycine inhibits activation of nuclear factor
kappa B and prevents liver injury in hemorrhagic shock in the rat.
Free Radic. Biol. Med., 2001, 31(10), 1236-1244.
[163] Nielsen, C.B.; Flyvbjerg, A.; Bruun, J.M.; Forman, A.; Wogensen,
L.; Thomsen, K. Decreases in renal functional reserve and proximal
tubular fluid output in conscious oophorectomized rats:
normalization with sex hormone substitution. J. Am. Soc. Nephrol.,
2003, 14(12), 3102-3110.
[164] Heyman, S.N.; Brezis, M.; Epstein, F.H.; Spokes, K.; Rosen, S.
Effect of glycine and hypertrophy on renal outer medullary hypoxic
 18 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0
injury in ischemia reflow and contrast nephropathy. Am. J. Kidney
Dis., 1992, 19(6), 578-586.
[165] Silva, P.; Rosen, S.; Spokes, K.; Epstein, F.H. Effect of glycine on
medullary thick ascending limb injury in perfused kidneys. Kidney
Int., 1991, 39(4), 653-658.
[166] Nagatomi, A.; Sakaida, I.; Matsumura, Y.; Okita, K.
Cytoprotection by glycine against hypoxia-induced injury in
cultured hepatocytes. Liver, 1997, 17(2), 57-62.
[167] Dong, Z.; Venkatachalam, M.A.; Weinberg, J.M.; Saikumar, P.;
Patel Y. Protection of ATP-depleted cells by impermeant
strychnine derivatives: implications for glycine cytoprotection. Am.
J. Pathol., 2001, 158(3), 1021-1028.
[168] Dong, Z.; Patel, Y.; Saikumar, P.; Weinberg, J.M.; Venkatachalam,
M.A. Development of porous defects in plasma membranes of
adenosine triphosphate-depleted Madin-Darby canine kidney cells
and its inhibition by glycine. Lab. Invest., 1998, 78(6), 657-668.
[169] Heyman, S.N.; Rosen, S.; Silva, P.; Spokes, K.; Egorin, M.J.;
Epstein, F.H. Protective action of glycine in cisplatin
nephrotoxicity. Kidney Int., 1991, 40(2), 273-279.
[170] Rivera, C.A.; Bradford, B.U.; Hunt, K.J.; Adachi, Y.; Schrum,
L.W.; Koop, D.R.; Burchardt, E.R.; Rippe, R.A.; Thurman, R.G.
Attenuation of CCl(4)-induced hepatic fibrosis by GdCl(3)
treatment or dietary glycine. Am J Physiol Gastrointest Liver
Physiol., 2001, 281(1), G200-G207.
View publication stats
Pérez-Torres et al.
[171] Chen, C.Y.; Wang, B.T.; Wu, Z.C.; Yu, W.T.; Lin, P.J.; Tsai,
W.L.; Shiesh, S.C. Glycine ameliorates liver injury and vitamin D
deficiency induced by bile duct ligation. Clin. Chim. Acta., 2013,
420, 150-154.
[172] Senthilkumar, R.; Nalini, N. Effect of glycine on tissue fatty acid
composition in an experimental model of alcohol-induced
hepatotoxicity. Clin. Exp. Pharmacol. Physiol., 2004, 31(7), 456-
461.
[173] Yin, M.; Ikejima, K.; Arteel, G.E.; Seabra, V.; Bradford, B.U.;
Kono, H.; Rusyn, I.; Thurman, R.G. Glycine accelerates recovery
from alcohol-induced liver injury. J. Pharmacol. Exp. Ther., 1998,
286(2), 1014-1019.
[174] Rose, M.L.; Madren, J.; Bunzendahl, H.; Thurman, R.G. Dietary
glycine inhibits the growth of B16 melanoma tumors in mice.
Carcinogenesis, 1999, 20(5), 793-798.
[175] Rose, M.L.; Cattley, R.C.; Dunn, C.; Wong, V.; Li, X.; Thurman,
R.G. Dietary glycine prevents the development of liver tumors
caused by the peroxisome proliferator WY-14,643. Carcinogenesis,
1999, 20(11), 2075-2081.
[176] McCole, D.F. The epithelial glycine transporter GLYT1: protecting
the gut from inflammation. J. Physiol., 2010, 588(Pt 7), 1033-
1034..
[177] Tariq, M.; Al Moutaery, A.R. Studies on the antisecretory, gastric
anti-ulcer and cytoprotective properties of glycine. Res. Commun.
Mol. Pathol. Pharmacol., 1997, 97(2), 185-198.