Pharmacology & Therapeutics 141 (2014) 150–159

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Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera

Associate editor: S. Kennedy

Existing and potential therapeutic uses for N-acetylcysteine: The need for
conversion to intracellular glutathione for antioxidant benefits
Gordon F. Rushworth a, Ian L. Megson b,⁎
a
Highland Clinical Research Facility, Centre for Health Science, Old Perth Road, Inverness IV2 3JH, UK
b
Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Centre for Health Science, Old Perth Road, Inverness IV2 3JH, UK

a r t i c l e i n f o a b s t r a c t

Keywords: N-acetyl-L-cysteine (NAC) has long been used therapeutically for the treatment of acetaminophen (paracetamol)
N-acetylcysteine overdose, acting as a precursor for the substrate (L-cysteine) in synthesis of hepatic glutathione (GSH) depleted
Glutathione through drug conjugation. Other therapeutic uses of NAC have also emerged, including the alleviation of clinical
Antioxidant symptoms of cystic fibrosis through cysteine-mediated disruption of disulfide cross-bridges in the glycoprotein
matrix in mucus.
More recently, however, a wide range of clinical studies have reported on the use of NAC as an antioxidant, most
notably in the protection against contrast-induced nephropathy and thrombosis. The results from these studies
are conflicting and a consensus is yet to be reached regarding the merits or otherwise of NAC in the antioxidant
setting.
This review seeks to re-evaluate the mechanism of action of NAC as a precursor for GSH synthesis in the context of its
activity as an “antioxidant”. Results from recent studies are examined to establish whether the pre-requisites for ef-
fective NAC-induced antioxidant activity (i.e. GSH depletion and the presence of functional metabolic pathways for
conversion of NAC to GSH) have received adequate consideration in the interpretation of the data. A key conclusion
is a reinforcement of the concept that NAC should not be considered to be a powerful antioxidant in its own right: its
strength is the targeted replenishment of GSH in deficient cells and it is likely to be ineffective in cells replete in GSH.
© 2013 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
2. Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
3. Clinical pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
152
4. Therapeutic uses of N-acetyl-cysteine: Licenced and potential . . . . . . . . . . . . . . . . . . . . . . . 154
153
5. Discussion and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
157
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
154
Author declaration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
154
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
157

1. Introduction
N-acetyl-L-cysteine (NAC) is a drug that was first reported to have
clinical benefit in the early 1960s, when it was shown to be an effective
Abbreviations: NAC, N-acetyl-L-cysteine; GSH, glutathione; GCL, glutamate cysteine li-
gase; ROS, reactive oxygen species; GSSG, glutathione disulfide; GSH Px, glutathione
peroxidises; COPD, chronic obstructive pulmonary disease; NAPQI, N-aceytl-p-
benzoquinonimine; IV, intravenous; CIN, contrast-induced nephropathy; IPF, idiopathic pul-
monary fibrosis; BAL, bronchoalveolar lavage; CF, cystic fibrosis; AKI, acute kidney injury.
⁎ Corresponding author at: Department of Diabetes and Cardiovascular Science,
University of the Highlands and Islands, Centre for Health Science, Inverness IV2 3JH,
UK. Tel.: +44 1463 279562; fax: +44 1463 711245.
E-mail address: ian.megson@uhi.ac.uk (I.L. Megson).
mucolytic agent in patients with cystic fibrosis (CF; Hurst et al., 1967).
The concept derived from the need to deliver reduced sulfhydryl moie-
ties to effect the disruption of disulfide bridges within the glycoprotein
matrix of mucus in CF patients. The amino acid residue, L-cysteine (Cys),
represents an obvious candidate for such an agent, but unfortunately, it
is susceptible to metabolism and undergoes rapid oxidation in solution,
generating the inactive disulfide, cystine (Cys–Cys). Acetylation of the
N-terminal of Cys was found to confer sufficient stability to the mole-
cule to facilitate delivery of reduced sulfhydryl (thiol) moieties to
work effectively as a mucolytic agent in this clinical setting.
During the 1970s, a substantial sequence of studies involving potential
sulfhydryl donor candidates was conducted in paracetamol poisoning.
However, other donors were either ineffective or provoked a significant

0163-7258/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pharmthera.2013.09.006
 G.F. Rushworth, I.L. Megson / Pharmacology & Therapeutics 141 (2014) 150–159
number of adverse effects (Prescott et al., 1976). A new and important
role for NAC emerged on account of subsequent studies investigating
its therapeutic potential in the treatment of acetaminophen (paraceta-
mol; N-acetyl-p-aminophenol) poisoning (Prescott et al., 1977, 1979).
The founding principle that underpinned the mechanism of action in
this setting was similar to that for CF: delivery of sulfhydryl moieties.
However, the mode of action of NAC in acetaminophen overdose was
thought to rely not only on the ability of NAC to offer some protection
against oxidation, but also through facilitation of rapid membrane per-
meability on account of the reduced polarity of the molecule compared
to the parent amino acid, Cys. Cleavage of the acetyl group is thought to
reveal free, reduced Cys, which is available for incorporation into the
highly abundant intracellular antioxidant, glutathione (GSH). The ben-
efit conveyed by NAC in the setting of acetaminophen overdose is to re-
plenish hepatic GSH that has become depleted through the use of the
tripeptide in the drug detoxification process. That NAC remains the
treatment of choice for acetaminophen overdose more than 50 years
after its first use is testament both to the importance of maintaining cel-
lular GSH reserves and to the exceptional qualities of NAC in helping to
replenish this key antioxidant when it has become acutely depleted.
Despite this, the precise pharmacological mechanisms that underpin
NAC activity are, as yet, not fully understood and may not even be
entirely related to GSH repletion (Waring, 2012; Gosselin et al., 2013).
Since the 1980s, there has been a growing interest in the therapeutic
potential of NAC in a range of diseases where oxidative stress is seen to
be a driver and in which antioxidant effects might convey benefit. The
original premise for believing that NAC might be effective as an antiox-
idant is unclear; perhaps its ability to drive synthesis of the powerful
antioxidant, GSH, in hepatic cells rendered deficient through acetamin-
ophen detoxification has been misconstrued as direct antioxidant capa-
bility, or maybe there is a general belief that all sulfhydryls will share
the antioxidant power of GSH. However, the evidence regarding the an-
tioxidant potential of NAC is that it is a relatively weak antioxidant:
direct experiments to assess its antioxidant potential suggest that
~10-fold more NAC is required compared to GSH to facilitate equivalent
oxygen-centred radical scavenging (Gibson et al., 2009), while the
ability of NAC to scavenge one of the major biologically relevant radical
species, superoxide, is not detectable (Aruoma et al., 1989). It is highly
likely, therefore, that the vast majority of the antioxidant effects attrib-
uted directly to NAC are actually mediated by increased intracellular
GSH. The distinction is important because it means that certain condi-
tions might have to be satisfied in order for NAC to confer antioxidant
activity: first, the enzymatic machinery necessary for GSH synthesis
must be intact and expressed at sufficient levels and second, it is likely
that GSH might have to be depleted for NAC to have any beneficial
effect. Far from being impediments to the use of NAC in a range of
clinical indications, these conditions for NAC antioxidant activity should
be viewed as positive indicators for use and could open the way to strat-
ified approaches for application of NAC only in those patients likely to
benefit.
This review will provide a brief overview of the biochemistry and
clinical pharmacology associated with NAC activity, followed by an eval-
uation of the licenced uses of NAC in clinical conditions worldwide and
an appraisal of the potential of NAC in novel indications, with a bias
towards those with an antioxidant component to the suggested mode
of action.
2. Biochemistry
Irrespective of the clinical target, the role of NAC is to deliver sulfhy-
dryl moieties for utilisation in biological processes. NAC has advantages
over Cys in this respect because it is relatively resistant to oxidation
to the disulfide and was originally believed to have the capability to
cross cell membranes without the need for amino acid transporters on
account of the reduced charge imparted by the acetyl moiety. However,
residual polarity of the NAC molecule on account of the –SH and –COOH
151
group would point to membrane permeation of intact NAC being
unlikely and studies with radio-labelled NAC would concur (Cotgreave
et al., 1987a). That said, low concentrations of NAC have been detected
in extracts of red blood cells from animals treated with NAC (Giustarini
et al., 2012), perhaps suggesting that a small proportion of NAC can per-
meate the membrane, assuming that extracts were not contaminated
with extracellular medium. The alternative is that extracellular deacety-
lation takes place and that Cys is taken into cells via amino acid trans-
porters. It remains unclear, therefore, as to the extent, means and
timing of the process of de-acetylation of NAC, but the assumption is
that, in the scenario whereby free intracellular reduced Cys is required
as a substrate for GSH synthesis, intact NAC penetrates the cell mem-
brane prior to hydrolysis to Cys in the intracellular environment, poten-
tially with the aid of N-deacetylases (Fig. 1). Data from an ongoing study
(Sandilands et al., 2012) might help to clarify whether a substantial pro-
portion of intact NAC accesses cells instead of being cleaved in the extra-
cellular environment, as has been suggested previously (Cotgreave
et al., 1991). For mucolytic effects of NAC, deacetylation may not be a
prerequisite, given that the sulfhydryl is available for interaction with
disulfide bridges irrespective of the presence of the acetyl group.
Glutathione (GSH) is a tripeptide that is synthesised and maintained
at high (mM) concentrations in cells (Meister & Anderson, 1983).
The rate limiting step of the synthesis involves conjugation of Cys with
L-glutamate (glutamate–cysteine ligase; GCL; (McPherson & Hardy,
2012), while L-glycine is added in a subsequent synthetic step involving
GSH synthase (GS; Fig. 2). In its reduced form, GSH has a wide variety of
functions, from antioxidant protection to protein thiolation and drug
detoxification, often supported by specific enzymes (Fig. 2).
Oxidative stress is a critical process that is implicit in the aetiology of a
wide range of diseases, including cardiovascular disease (Le Brocq et al.,
2008), diabetes (Stadler, 2012) and cancer (Sosa et al., 2013). GSH is a
critical intracellular antioxidant that helps to limit the impact of oxidative
stress and to protect vital cellular components (lipids, proteins, DNA)
against harmful peroxidation. The antioxidant effects of GSH rely on
the presence of the free sulfyhydryl group as a ready source of reducing
equivalents to quench radical species. As well as acting as a direct
“sacrificial” scavenger of potentially harmful reactive oxygen species
(ROS), GSH provides reducing equivalents to support the antioxidant
Fig. 1. N-acetyl-L-cysteine (NAC): a cysteine pro-drug.
152 G.F. Rushworth, I.L. Megson / Pharmacology & Therapeutics 141 (2014) 150–159
activity of GSH peroxidases (GPx; Pompella et al., 2003), a powerful de-
fence against peroxides (R-OOH, e.g. hydrogen peroxide, HO-OH). GSH
is oxidised to the thiyl radical (GS•) in the process, which rapidly
dimerises to form the glutathione disulfide (GS-SG; Equation 1).
Equation 1: Antioxidant effect of GSH/GPx on peroxides
GSH also reacts with another important cellular oxygen-centred free
radical, superoxide (O2•−), but while the reaction oxidises GSH, it is
thought that superoxide is regenerated in the process (equation 2;
Winterbourne & Metodiewa, 1999). In this regard, it is thought essential
that GSH acts in concert with superoxide dismutases (SOD), perhaps
explaining the co-location of the two antioxidants, particularly in mito-
chondria. The same process is central to the reaction of superoxide with
NAC, but not with Cys, where hydrogen peroxide is a product instead of
superoxide (Winterbourne & Metodiewa, 1999).
Equation 2: Reaction of thiols with superoxide: GSH is consumed, but
superoxide is regenerated (adapted from Winterbourne & Metodiewa,
1999). This process is the same for NAC, but different for cysteine,
where H2O2 is generated instead of superoxide
One of the greatest strengths of GSH over most other antioxidant de-
fences is the intracellular capability to regenerate the reduced form
from the disulfide via the action of GSH reductase (GR). There is some
evidence to suggest that GSH can also contribute to recycling of the di-
etary antioxidants vitamins C (Li et al., 2001; Montecinos et al., 2007),
which has the redox potential to recycle vitamin E in turn (Halpner
et al., 1998; May et al., 1998; Fig. 2). In this sense, GSH might be seen
as the cornerstone of antioxidant defence.
Critically, however, GSH synthesis is understood to be self-regulated
(Meister & Anderson, 1983; Griffith, 1999); that is to say that the rate-
limiting enzyme for its synthesis (GCL) is inhibited by the product
(GSH; Fig. 2). In addition, expression of GSH-related enzymes, including
those involved in its synthesis, are subject to complex regulation driven
by the intracellular redox state (Arrigo, 1999; Dickinson et al., 2004);
ageing and certain disease states are well-known to suppress GCL
expression (Lu, 2009). These are important considerations with respect
to the impact of NAC as a therapy: substrate might not be rate-limiting
in conditions where GCL expression is suppressed. On the other hand, in
cells where GSH is already abundant, feedback inhibition of synthesis
could negate any benefits of NAC delivery that require GSH generation.
2.1. Considerations for N-acetylcysteine as a direct antioxidant
The ability of a substance to act as an antioxidant in a biologically
relevant situation is a highly complex concept, but one that is central
to understanding the mode of action of NAC in many of its potential
therapeutic uses. In this respect, the location of ROS generation, the
ROS species generated, the relative abundance of endogenous antioxi-
dants in the locality, the rate constants of endogenous antioxidants for
the ROS generated, together with their relative concentrations, will all
be vital determinants of the success or failure of an administered antiox-
idant in helping to prevent cellular damage. Often, however, many of
these details are not known, making selection of an appropriate antiox-
idant for a specific condition difficult. Attempts to rank antioxidants
according to their known characteristics (rate constants and concentra-
tion) have been made, but are fraught with difficulties, not least because
of the variability in estimates for rate constants for reactions with radi-
cal species, as highlighted in (Winterbourne & Metodiewa, 1999). NAC,
has particularly high rate constants for •OH (~1010 M−1 s−1), CO3•−,
•NO2 and HOCl (all ~107 M−1 s−1; Samuni et al., 2013), but it is fair to
say that NAC does not rank highly amongst antioxidants in general, or
even amongst endogenous thiols (Winterbourne & Metodiewa, 1999),
particularly when concentration and location are taken into account.
The case is most evident in the intracellular compartment, where the
overwhelming antioxidant potential of GSH, ascorbate and specific anti-
oxidant enzymes (e.g. superoxide dismutases, glutathione peroxidases,
catalase) ensure that the very low (if any) concentrations of NAC that
persist inside cells are unlikely to contribute directly to antioxidant ca-
pacity. The same is true in the plasma compartment in cases where
NAC is administered orally and concentrations only reach low μM; plas-
ma antioxidant capacity has been found to be unchanged by treatment
(Leelarungrayub et al., 2011). However, IV delivery might have the
capability to increase the plasma sulfhydryl load sufficiently to impact
on plasma antioxidant capacity. Plasma NAC can reach low mμM con-
centrations, compared with 3–5 μM GSH, ~250 μM cysteine, 600 μM
albumin sulfydryl (Cys 34), N50 μM ascorbate and ~400 μM urate. The
thiol pool and antioxidant potential is therefore dominated by albumin
(Turell et al., 2013) and there are few data available to indicate whether
intravenous NAC can influence plasma total antioxidant capacity. Per-
haps surprisingly, plasma antioxidant capacity with NAC is rarely mea-
sured and, when it is, the data fail to show a convincing impact
(Buyukhatipoglu et al., 2010). The theoretical impact of NAC on plasma
antioxidant benefit is dependent on NAC remaining in the reduced state
and on the blood being the principal source of the target ROS. Any direct
antioxidant effect could be supplemented by an indirect benefit that
might be realised through chelation of metal ions (Lodge et al., 1998;
Joshi et al., 2010) capable of mediating Fenton Chemistry and formation
of hydroxyl radical, but again there are specific chelators for commonly
occurring metals (e.g. iron and copper) in the blood (e.g. ferritin,
caeruloplasmin respectively) that would effectively compete with NAC
in this regard, unless already saturated or under-expressed. NAC has,
however, been shown in animal experiments to increase excretion
rates of some metal complexes (borate and chromate), but the mecha-
nism underpinning the effect is unclear (Banner et al., 1986). More
comprehensive evidence is available to support a direct chelating
effect of NAC with methyl mercury to form S-conjugates (Zalups &
Ahmad, 2005), although at the cellular level, protection against methyl
mercury-induced toxicity is primarily modulated by intracellular GSH,
which can be supplemented by NAC (Kaur et al., 2006; Becker &
Soliman, 2009). While NAC therefore has the capability to form S-
conjugates with some metals, it is unclear as to the importance of this
mechanism in driving any protective effects compared to intracellular
GSH acting either as a chelating agent itself or as an antioxidant to ame-
liorate downstream oxidative stress. Indeed, there is some evidence to
suggest that formation of S-conjugates of mercury with NAC, Cys or ho-
mocysteine can facilitate uptake of mercury into renal tubular cells, with
the potential for detrimental effects (Zalups & Barfuss, 1998; Brandao
et al., 2006). There are limited clinical data available to evaluate the po-
tential of NAC in treating metal toxicity (Blanusa et al., 2005); a case
study from 1984 did suggest benefit of NAC by haemodialysis in methyl
mercury poisoning (Lund et al., 1984), but the dearth of subsequent
clinical data might point to a lack of clear benefit in this arena.
 G.F. Rushworth, I.L. Megson / Pharmacology & Therapeutics 141 (2014) 150–159
Fig. 2. Impact of NAC on synthesis and utilisation pathways for GSH. De-ACase — deacetylases; GCL — glutathione cysteine ligase; GS — glutathione synthase; GPx — glutathione
peroxidase; GR — glutathione reductase; GST — glutathione-S-transferase; γ-GT — glutamyl transpeptidase.
2.2. Antioxidant and glutathione-independent effects of N-acetyl-cysteine
A final consideration with respect to the antioxidant potential of
NAC is true of any antioxidant – how much is too much? The barrier
function of antioxidants dictates that higher concentrations are likely
to be more effective. However, it is also clear that very high concentra-
tions of antioxidants at least have a theoretical potential to generate a
counter-intuitive pro-oxidant effect, probably mediated via reduction
of transition metal ions and enhancement of Fenton Chemistry
(Halliwell, 1996). How important this effect is in vivo is not understood,
but it is likely that there is an optimal concentration for NAC in the plas-
ma, as there is thought to be for other antioxidants.
Data from a wide range of in vitro studies suggest that NAC might
have the capability to alter protein structure and/or function, perhaps
via reduction of disulfide bridges and conformational change. Examples
include modulation of angiotensin II receptor binding in vascular
smooth muscle cells (Ullian et al., 2005) and altered cytokine affinity
of TNF-α receptors (Hayakawa et al., 2003). While the results from
these studies are interesting from a theoretical perspective, the concen-
trations of NAC used are extremely high (typically ~10 mM and some-
times as high as ~100 mM), so their relevance to the in vivo situation
should be considered with some caution.
3. Clinical pharmacology
While depletion of GSH is a feature of many disease states and its re-
plenishment is desirable, administration of GSH per se is not considered
optimal on account of its poor bioavailability and its limited ability to
cross the phospholipid bilayer of cells. Likewise, delivery of Cys suffers
from rapid oxidation to its disulfide, cystine, which has poor solubility
and renders the crucial sulfhydryl functional group at least temporarily
inaccessible. As a result, other means of sulfhydryl delivery have been
developed to circumvent this problem (Suzuki, 2009). NAC is the most
153
enduring delivery mode for Cys; the initial indication for prescribing
was as a mucolytic because it was reported to break down the disulfide
bridges in mucus glycoproteins to reduce viscosity for those with em-
physema predominant chronic obstructive pulmonary disease (COPD;
(Aitio, 2006). Oral and aerosol preparations of NAC are licenced for
use in some countries, but not worldwide e.g. UK has no licenced uses
for oral NAC, where carbocysteine (an established mucolytic with simi-
lar mechanism of action) is preferred for lung conditions. After oral ad-
ministration (typically 600–1200 mg pills up to 3 times daily), NAC is
rapidly absorbed, with peak plasma concentrations (low micromolar)
seen between 30 min and 1 h (Holdiness, 1991). Orally administered
NAC is absorbed in the small intestine and undergoes first-pass hepatic
metabolism to Cys, from which the liver synthesises GSH. Hepatic stores
of GSH are replenished before GSH is released into the plasma via a
membrane transporter (Bartoli & Sies, 1978). Oral bioavailability is con-
sidered to be low (b10%), potentially on account of gut-wall metabolism
and high first-pass metabolism (Borgstrom et al., 1986; Olsson et al.,
1988). However, it is also possible that low plasma detection is due to
rapid diffusion into cells and conversion to GSH, maintaining a constant
concentration gradient across the membrane.
The intravenous preparation of NAC bypasses first-pass and gut-wall
metabolism, delivering sufficient concentrations (high micromolar/low
millimolar) expeditiously in acute acetaminophen overdose. It will
be interesting to discover from an ongoing direct comparison of oral
versus intravenous NAC, whether intracellular GSH supplementation
is greater with substantially higher NAC delivery via the intravenous
route (Sandilands et al., 2012). There is some evidence to suggest that
hepatocellular concentrations of NAC are actually increased on oral
administration, compared with IV, as a result of first-pass portal circula-
tion (Green et al., 2013).
Adverse effects experienced with NAC are somewhat dependent on
the route of administration used. Mild reactions – such as nausea,
vomiting and cutaneous reactions (pruritus and erythema) – are common
154 G.F. Rushworth, I.L. Megson / Pharmacology & Therapeutics 141 (2014) 150–159
with the IV preparation (Sandilands & Bateman, 2009). Severe systemic
reactions are uncommon, but are thought to be non-immunological
(non-IgE mediated) in nature and are therefore defined as anaphalactoid
reactions which are reported in 20% of patients, where reactions are
more likely to occur in patients with comparatively low acetaminophen
concentrations or past history of asthma (Pakravan et al., 2008; Waring
et al., 2008). Anaphalactoid symptoms include flushing, pruritus,
angiodema, bronchospasm and hypotension (Flanagan & Meredith,
1991). There is an increased risk of anaphylactoid side effects with
intravenous compared to oral delivery (Kanter, 2006), most likely on
account of the much higher plasma concentrations achieved. Indeed,
the reactions are most prevalent immediately after the initial loading
infusion.
4. Therapeutic uses of N-acetyl-cysteine: Licenced and potential
4.1. Cystic fibrosis and other lung diseases
Genetic mutation to the gene encoding the cystic fibrosis transmem-
brane conductance regulator (CFTR), which functions as a cAMP chlo-
ride channel in healthy lung cells, is responsible for cystic fibrosis
(CF; Rowe & Clancy, 2006). This aberration leads to an alteration in
trans-epithelial ion transport, electrolyte balance and fluid content in
a range of tissues. The effect is most evident in the lung, where viscous
mucus production is prolific, difficult to clear and susceptible to repeat-
ed chronic infection. Inflammation in response to iterative cycles of
infection manifests in lung damage and fibrosis, culminating in respira-
tory failure and mortality.
The impact of NAC in the CF setting is likely to be multifactorial. First, it
is believed to act as a mucolytic agent, delivering Cys residues to break
sulfhydryl bridges between glycoproteins in mucus (Sheffner et al., 1964).
Equation 3: Cys-mediated cleavage of disulfide bridges in proteins/
peptides/glycopeptides
However, it is also likely that NAC might have several supplementary
actions mediated by enhancement of intracellular GSH, the major anti-
oxidant in lung tissue (Rahman & MacNee, 2000). It has been found that,
because exocytosis of GSH is thought to be dependent on the same
channel that is dysregulated in CF (Dauletbaev et al., 2004), GSH in
bronchoalveolar lavage (BAL) fluid has been found to be depressed
(Gao et al., 1999) and after oral administration, free NAC could not be
identified in BAL fluid (Cotgreave et al., 1987b). However, measures in
sputum from CF patients suggest that GSH is elevated in this matrix
and a sufficient proportion of it is in the reduced form to confer antiox-
idant activity (Dauletbaev et al., 2004). The possibility also exists,
however, that increased intracellular GSH on account of NAC treatment
might protect against the neutrophil-driven generation of ROS that
mediate the longer-term tissue damage and fibrosis in CF (Ratjen &
Grasemann, 2012). In addition, doses of N1.8 g/day have been shown
to act to reduce the migration of neutrophils to the lungs, to restrict neu-
trophil access through narrowing of lung capillaries and to increase
intra-neutrophil GSH (Tirouvanziam et al., 2006). Another small phase
II clinical study investigated the safety and efficacy of low-dose
(700 mg/day) vs. high-dose (2800 mg/day) NAC over a 12 week peri-
od, where the high-dose regimen was found to be safe and efficacious
(Dauletbaev et al., 2009). NAC has also been found to increase sputum
penetration by DNA nanoparticle formulations (Suk et al., 2011).
The potential benefits of NAC have also been evaluated in a number of
other respiratory diseases, including COPD, which may be characterised,
in part, by chronic mucus production, leading to an increased risk of
infection. The benefits of long and short-term administration of NAC
for bronchial hypersecretion in chronic bronchitis have been known
since the early 1980s (Multicentre Study Group, 1980; Tattersall et al.,
1983). A subsequent systematic review, which focused specifically on
NAC, acknowledged the beneficial effects of oral administration for
treatment periods of 3–6 months for reducing exacerbations and im-
proving symptoms of chronic bronchitis (Stey et al., 2000). However,
the results of the review were uncertain as to the long-term benefits
in all patients with chronic bronchitis. A subsequent systematic review
of mucolytics in chronic bronchitis or COPD began to stratify where mu-
colytics might be found to be most cost-effective, advocating their use in
patients with severe COPD who are susceptible to repeated exacerba-
tions (Poole & Black, 2001).
Asthma is defined as a reversible airways obstruction where chronic
inflammation and airway hypersensitivity lead to symptoms of breath-
lessness and wheeze in patients. Inflammation in asthma has been in-
part shown to be mediated by ROS (Dworski, 2000). It has been postu-
lated that the actual antioxidant imbalance must be known in order to
deliver targeted exogenous antioxidant therapy (Kirkham & Rahman,
2006), suggesting that NAC therapy might not be appropriate in every
case. However, in vitro studies of antioxidant use in asthma have, to-
date, not shown any definitive benefits; it has been postulated that this
lack of clinical efficacy is due to a lack of evidence base from which anti-
oxidant type and dose were chosen from in vivo studies (Dworski, 2000).
4.2. Acetaminophen overdose and drug poisoning
Acetaminophen is a relatively safe and effective medication when
used at appropriate doses. However, hepatocellular necrosis can result
from either single or repeated doses of 10–15 g over 24 h in adult pa-
tients of normal body weight in the absence of enzyme-inducing drugs
(Ryan, 2012). Acetaminophen is rapidly absorbed and undergoes first-
pass metabolism in the liver, one of the P450-derived by-products of
which is the potentially toxic metabolite, N-aceytl-p-benzoquinonimine
(NAPQI; Dart et al., 2006). NAPQI is normally detoxified via conjugation
to GSH in preparation for excretion in the urine, but overdose results in
hepatocellular damage on account of depletion of hepatic GSH, leading
to protein binding and cellular dysfunction (Saito et al., 2010).
Administration of NAC in acetaminophen poisoning acts to rapidly
increase hepatic GSH synthesis and reduce protein binding (Saito
et al., 2010). The requirement for NAC is determined by plotting the
plasma level of acetaminophen against the time post-overdose on a
nomogram; effectiveness of NAC therapy diminishes with time after
acetaminophen overdose. The primary target is to initiate NAC treat-
ment within 8 h to minimise the risk of hepatocellular damage (Gray
et al., 2011), but reports indicate that administration of NAC after 10 h
can still reduce mortality (Harrison et al., 1990). For practical reasons,
in remote and rural areas, or when a blood sampling is unavailable,
the recommended treatment for acetaminophen overdose is methio-
nine, although evidence of efficacy is lacking.
Oral NAC (where available) has been found to be as effective as in-
travenous NAC up to 10 h post-overdose. However, use of activated
charcoal in the accident & emergency department can decrease the
absorption of orally administered NAC. Therefore, the preferred route
of administration (indeed the only licenced route available in the UK)
is IV NAC (Nambiar, 2012). Despite arguments for and against the use
of IV over oral formulations of NAC, there have been no robust clinical
studies to test for the optimal route and duration of treatment (Chyka
et al., 2000). In part, this is due to the requirement for a large sample
size to show a difference between these two routes of administration
(Waring, 2012).
The arrival of intravenous acetaminophen has also heralded a new set
of concerns relating to potential overdose. Intravenous administration
errors, together with a lack of understanding of dosage reductions re-
quired for underweight patients is also thought to contribute to the po-
tential risk of this formulation. Malnourished or perioperative patients
 G.F. Rushworth, I.L. Megson / Pharmacology & Therapeutics 141 (2014) 150–159
who may have diminished stores of GSH have also been postulated to be
particularly susceptible to hepatocellular damage (Gray et al., 2011).
4.3. Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) or cryptogenic fibrosing alveoli-
tis is an interstitial lung disease of progressive nature. The median sur-
vival from onset of dyspnoea is limited at 3–6 years (Nicholson et al.,
2000). Originally, disease progression was thought to occur after an in-
flammatory reaction, the termination of which results in fibrotic lesions.
However, this hypothesis has now been challenged and current dogma
points to cellular changes in response to chronic alveolar epithelial
injury (Lota & Wells, 2013).
The presence of an imbalance between oxidants and antioxidants in
IPF was first reported in the 1980s. Lung epithelial cells obtained from
BAL have been found to contain oxidants at cytotoxic levels (Cantin
et al., 1987) and GSH was found to be depressed within the epithelial
lining fluid (Cantin et al., 1989). The results of two small studies in pa-
tients with IPF found that administration of oral NAC (600 mg three
times a day) increased the levels of GSH in BAL (Behr et al., 1997;
Meyer et al., 1994). The IFIGENIA trial reported improvements in the
12 month vital capacity and carbon monoxide diffusing capacity in IPF
patients prescribed high-dose oral NAC (600 mg three times a day) in
addition to prednisolone and azathioprine (Demedts et al., 2005). How-
ever, there have been some concerns over the design of the trial due to
the relatively small numbers of patients it recruited (Fioret et al., 2011).
It is also worth noting that there is little published evidence for the use
of prednisolone and azathioprine in this indication (Rudd et al., 2007;
Maher, 2011) and it has been suggested the benefits of NAC may be as
a result of the protective benefits of NAC with regard to azathioprine
toxicity. Interestingly, when the effect of intravenous NAC administra-
tion at a range of doses was compared between patients with known
IPF and healthy volunteers, there was no difference in the GSH levels
noted in the healthy volunteer group (Meyer et al., 1995), reinforcing
the concept that NAC only elicits an effect to replenish GSH levels in
tissue that is deficient in the tripeptide.
A more recent study, PANTHER-IPF, was set up to investigate the
safety and efficacy of the triple therapy combination of prednisolone,
azathioprine and NAC. The study was designed with three arms: triple
therapy, NAC-alone and a placebo group. An interim analysis was
published in 2012 which reported an increased mortality rate (8 vs 1
death, p = 0.01) and hospitalisation (23 vs 7, p b 0.001) in those
patients on the triple therapy arm: this arm was subsequently stopped
early due to safety concerns and the authors state that the combination
should not be used in these patients (Raghu et al., 2012).
4.4. Contrast-induced nephropathy (CIN)
CIN is a serious adverse condition that develops in response to con-
trast media administered to patients during radiological procedures,
such as computed tomography or angiography. The clinical definition
of CIN is a ≥25% increase in serum creatinine compared to baseline
(Parfrey, 2005). Within secondary care settings, an increase in morbid-
ity and mortality has been realised as a result. The risk of developing CIN
increase in the presence of pre-existing risk factors for the development
of renal impairment, for example in those with cardiovascular or renal
co-morbidities (particularly diabetic nephropathy) or in the elderly
(Jo, 2011); the risk to patients with normal renal function and without
risk factors for developing CIN is small (Parfrey, 2005). However, a
recently published retrospective study investigating the incidence of
acute kidney injury after radiological procedures either with or without
contrast was unable to find a causal link between intravenous contact
and acute kidney injury, even in groups previously considered to be at
risk (McDonald et al., 2013).
The aetiology of CIN is not fully understood, but it is thought to relate
to two separate mechanisms – haemodynamic changes and renal
155
tubular toxicity (Parfrey, 2005). Administration of contrast media alters
the normal haemodynamic processes within the kidney. Initially, system-
ic vasodilation causes a decrease in renal blood flow which ultimately
results in vasoconstriction of the efferent arteriole to maintain renal out-
put and promote excretion of contrast. In addition to the haemodynamic
changes, toxic effects of contrast media in the renal tubules result in
inflammation and renal tubular necrosis. The degree of nephrotoxicity
experienced after administration of contrast media varies widely from
those who are asymptomatic to those who will require dialysis.
Ensuring adequate hydration with isotonic saline is currently the
standard practice as preparation for patients about to undergo a radio-
logical scan involving the administration of contrast media. A number
of alternative pharmacological agents have been investigated for use
in CIN. Ostensibly, agents have been trialled for this indication as a result
of their vasodilatory characteristics and these include the use of calcium
channel blockers, theophylline and dopamine (Jo, 2011) although none
have been shown to be efficacious.
NAC has been the subject of a series of trials in this arena, with mixed
results. There have been four recent trials published which demonstrate
significant reductions in CIN for those patients treated with intravenous
NAC versus control groups (Baker et al., 2003; Carbonell et al., 2010; Hsu
et al., 2012; Koc et al., 2012). Another clinical study has reported a sig-
nificant NAC-induced decrease in serum creatinine, urinary markers of
oxidative stress and renal tubular injury (Drager et al., 2004). However,
a number of studies have failed to show benefit of NAC in this setting: a
study in 80 patients with chronic renal insufficiency (Goldenberg et al.,
2004) failed to show a difference between oral NAC (600 mg 3 times a
day) compared to placebo for the primary end point of acute contrast-
induced increase in serum creatinine. A similar lack of efficacy for NAC
was noted in a study of 10,574 patients undergoing percutaneous
coronary intervention (Gurm et al., 2012). In a recent study comparing
intravenous and intrarenal administration of NAC/placebo as CIN pro-
phylaxis in patients with ST-elevation myocardial infarction undergoing
primary angiography, there was no effect of NAC in the prevention of
CIN (Aslanger et al., 2012). It should be noted that patients were select-
ed for this study based on the index event rather than pre-existing renal
insufficiency, diabetes or chronic cardiac condition. Inappropriate dos-
age and/or route of NAC administration have been cited as potential rea-
sons for the lack of efficacy of NAC in some studies (Shalansky et al.,
2005), but little attention appears to have been paid to the fundamental
premise for NAC antioxidant activity – is GSH depressed in renal tissue
of patients? This aspect, above all, might help to explain the inconsistent
results because the GSH status in renal patients is likely to be closely re-
lated to each individual's specific disease aetiology. The relative success
of any given clinical study is likely to hinge on the proportion of patients
with depleted GSH, but with the necessary enzyme complement to
actively convert NAC to GSH.
A recent meta-analysis on the use of intravenous NAC in CIN was in-
conclusive; the results showed a tendency towards a beneficial effect of
NAC administration, but were not significant (p = 0.06; Sun et al.,
2013). The authors commented on the heterogeneity of the trials within
the meta-analysis and have called for a large-scale, well designed study
to investigate the potential for IV NAC in CIN.
Overall, due to its low acquisition cost and relative ease of adminis-
tration and despite the inconclusive evidence in favour of its use, intra-
venous NAC as a prophylactic agent for prevention of CIN is advocated
by a number of centres. There is a requirement for further research in
this area to determine if there is any long-term benefit of the prophylac-
tic treatment. An ongoing study to investigate the effect of NAC in
healthy volunteers and patients with renal failure exposed to contrast
medium might shed further light on the issue (Sandilands et al., 2012).
4.5. Cardiovascular disease and diabetes
Oxidative stress is a key component in the atherogenic process,
resulting in the oxidation of lipids in low density lipoproteins (LDL)
156 G.F. Rushworth, I.L. Megson / Pharmacology & Therapeutics 141 (2014) 150–159
and rendering them recognisable to macrophages prior to ingestion
and formation of resident foam cells in the vessel wall (Griendling &
Alexander, 1997). Research has shown that that there is a depletion
of GSH in blood vessels from atherosclerotic mice from a very early
age (Biswas et al., 2005) and an imbalance, and in some cases a com-
plete absence, of GPx activity, indicating the lack of an antioxidant reg-
ulator of oxidative stress in cells associated with human atherosclerotic
plaque (Lapenna et al., 1998). Furthermore, macrophage GSH and GPx
concentrations are inversely related to oxidation of LDL cholesterol,
whereby low concentrations of the antioxidants lead to an increase in
lipoprotein oxidation (Rosenblat & Aviram, 1998). As well as GSH deple-
tion associated with atherosclerotic plaques, there is also evidence that
GSH is depressed in platelets in conditions associated with increased
risk of thrombosis. Principal amongst these is diabetes (both type 1
and type 2), where hypersensitivity of platelets to thrombotic stimuli
has been linked to low intraplatelet GSH levels (Mazzanti & Mutus,
1997). The potential for platelet GSH as a therapeutic target is supported
by animal experiments in which high dose NAC was found to improve
endothelial function (Pieper & Siebeneich, 1998).
A number of clinical studies to investigate the potential for NAC as a
therapeutic agent have been conducted in a type 2 diabetes population.
This is a particularly important target group on account of the increased
risk of cardiovascular disease in diabetes, coupled with the lack of effi-
cacy of aspirin in primary prevention of cardiovascular complications
amongst these patients. First, it has been shown that 6 month treat-
ment with a combination of L-arginine (to prime synthesis of the
endothelium-derived vasodilator, nitric oxide; NO) with NAC reduced
blood pressure by ~5 mmHg in patients with type 2 diabetes and hyper-
tension (Martina et al., 2008). Meanwhile, several other studies focused
on the impact of NAC in platelet function: Gibson et al. demonstrated
that NAC increased intraplatelet levels of GSH, decreased ROS detection
and reduced platelet activation in vitro (Gibson et al., 2011). Leading on
from this observation, the antiplatelet properties of NAC were trialled
in vivo in a cohort of type 2 diabetes patients (Treweeke et al., 2012).
The study reported an inhibition of platelet–monocyte conjugation, a
surrogate marker of cardiovascular risk, within 2 h of administration,
an effect that was maintained following daily self-administration over
a 1 week period. Crucially, however, the use of platelets in this study
facilitated measurement of GSH in the target cells and found that NAC
was most effective at reducing platelet–monocyte conjugation in
those patients with the most depleted platelet GSH; patients with plate-
lets replete in GSH at baseline received no benefit from NAC treatment
and did not experience a rise in platelet GSH. This result reinforces
the notion that stratification of patients prior to treatment with NAC
is essential to ensure successful treatment: the evidence from a wide
range of sources strongly suggests that NAC will be ineffectual in
those patients in whom GSH is not depleted in the target tissue.
4.6. Carcinogenesis and cancer
The anti-carcinogenic properties of NAC have been reported since
the early1980s (De Flora et al., 1984, 1985). These properties are pleio-
tropic, ranging from benefits of NAC in preventative, pre-neoplastic and
cancer treatment stages. It is thought that NAC elicits its anticarcinogen-
ic actions via a number of different physiological processes including the
attenuation of genotoxic ROS, induction of DNA repair, and regulation of
carcinogen-induced apoptosis (De Flora et al., 2001).
Clinical studies investigating NAC as a potential chemopreventive
agent were first conducted in the 1990s. A phase I study reported that
significant toxic effects were noted in subjects exposed to doses of NAC
(after titration phase, total daily oral dose was 6400 mg/m2) which
were deemed to be biochemically effective (Pendyala & Creaven,
1995). Since the publication of this study, a phase II trial, EUROSCAN,
conducted in patients with head and neck or lung cancer has also report-
ed (van Zandwijk et al., 2000). This study used a much smaller dose of
600 mg/day oral NAC for 2 years. The study failed to show any significant
decrease in the primary end points which were survival, event-free sur-
vival or secondary primary tumours.
NAC has also been investigated as a potential agent to attenuate side
effects of platinum-based chemotherapy. One study in rats suggests that
NAC blocks oxidative stress to reduce cisplatin-induced acute renal im-
pairment (Luo et al., 2008). A recent small clinical study in 84 patients
has reported that transtympanic injections of NAC appear to prevent
cisplatin-induced ototoxicity (Riga et al., 2013).
4.7. Human immunodeficiency virus
Two key papers reported in the late 1990s that low GSH
(Herzenberg et al., 1997) or thiol levels (Marmor et al., 1997) may be
used as a predictor or decreased survival in patients with human immu-
nodeficiency virus (HIV) infection. Subsequently, an 8 week double-
blind, placebo-controlled clinical trial identified that oral NAC could
safely replenish whole blood GSH and T-cell GSH in patients with HIV
infection (De Rosa et al., 2000). This study was not designed to investi-
gate any potential clinical benefits in survival, but the emergence of de-
pleted GSH as a feature in HIV infection would certainly merit further
exploration of the potential benefits of NAC in this setting.
4.8. Neuropsychiatric disorders
GSH depletion is a feature of a wide range of neuropsychiatric disor-
ders, including Alzheimer's, Parkinson's and Huntingdon's diseases
(Johnson et al., 2012). Although there are subtle differences in GSH
handling within the central nervous system compared to other tissues,
the basic concepts are the same: GSH is predominantly synthesised in
the cytoplasm of cells and is dependent on influx of Cys to drive the
rate-limiting step of GSH synthesis. The principal player in transport
of Cys into neurones is the excitatory amino acid transporter C1
(ECAAC1); astrocytes also employ cystine/glutamate (Xc−) antiporters
to supplement the intracellular thiol pool. GSH concentrations in cere-
brospinal fluid are similar to those in blood (~5 μM) and evidence for
transit of GSH across the blood–brain-barrier seems unlikely.
Given that Cys is central to neuronal GSH synthesis, NAC has been
trialled in a number of neuropsychiatric disorders where redox imbal-
ance has been implicated in the aetiology. In some instances, there has
been a suggestion that NAC might be useful in this setting, not only on
account of repletion of GSH, but also because NAC-derived cystine has
the potential to lead to an increase in release of glutamate from astro-
cytes via the Xc− antiporters, resulting in activation of neuronal gluta-
mate receptors, resulting in dopamine release (Dean et al., 2011).
A number of small clinical studies and case reports have cited the
utility of NAC in a variety of neuropsychiatric conditions from addiction
(Mardikian et al., 2007; Knackstedt et al., 2009; Gray et al., 2010) to
schizophrenia (Lavoie et al., 2008; Berk et al., 2008b), obsessive compul-
sive disorder (Lafleur et al., 2006), bipolar disorder (Berk et al., 2008a,
2011) and even as a neuroprotective agent in Alzheimer's disease
(Adair et al., 2001). Redox imbalance and, more specifically, intracellu-
lar GSH depletion has been implicated in autism, prompting a more
recent randomized, placebo-controlled trial to determine the impact
of oral NAC (900 mg self-administered once daily for 4 weeks, then
twice-daily for 4 weeks and three times daily for 4 weeks; 31 patients,
14 randomized to NAC available for follow-up) on children with autism
(Hardan et al., 2012). The trial found a substantial and significant
improvement in irritability, measured as one of several parameters
on the Aberrant Behaviour Checklist (ABC). NAC was not, however,
shown to increase survival in patients with amyotrophic lateral sclerosis
(Louwerse et al., 1995).
Clinical data are therefore beginning to accumulate to support posi-
tive findings in animal studies and to suggest therapeutic potential for
NAC in a wide range of neurological disorders in which oxidative stress
is implicated. While the studies to date are, on the whole, encouraging,
they are typically small and require confirmation in larger studies. Of
 G.F. Rushworth, I.L. Megson / Pharmacology & Therapeutics 141 (2014) 150–159
particular interest will be clarification of whether NAC itself is able to
cross the blood brain barrier or whether benefits are realised through
simply increasing the Cys pool in the blood, leading to the necessary
increase cysteine in cerebrospinal fluid to fuel intra-neuronal GSH
synthesis.
5. Discussion and conclusions
It is vital to think of NAC as a pro-drug, the actions of which are al-
most exclusively driven by, and dependent on, successful conversion
to the powerful detoxifying agent and antioxidant, GSH. In those thera-
peutic targets where an antioxidant activity is the principal mode of
activity, it is apparent that intracellular incorporation into GSH is vital
for efficacy. The success of NAC in acetaminophen overdose is testament
to this concept: there is an absolute requirement for de novo synthesis
of GSH to replace that used to detoxify the NAPQI metabolite in these
patients. In this setting, there is no question that NAC is a life-saving
drug, with the only apparent limitation in its efficacy related to the
time delay between overdose and therapy.
NAC is often referred to as a “powerful antioxidant”, a misconception
that has potentially fuelled many of the studies associated with indica-
tions other than acetaminophen overdose. NAC in itself has some
antioxidant potential, but it is a much weaker antioxidant than GSH
and most, if not all, of the other endogenous antioxidant agents and
enzymes. This knowledge, coupled with the relatively low plasma con-
centrations that are achievable with intravenous (100–500 μM) and
certainly oral (b5 μM) dosing points to the fact that NAC itself is unlikely
to contribute significantly to antioxidant defence. Similarly, Cys gener-
ated through hydrolysis of NAC is rapidly oxidised to cystine with the
loss of any antioxidant potential. Instead, the antioxidant potential of
NAC is in the provision of substrate for synthesis of intracellular GSH,
present in healthy cells at millimolar concentrations. Rapid conversion
of NAC in GSH-deficient cells maintains a steep concentration gradient
across the membrane, and drives sufficient accumulation of GSH to re-
store the concentration to healthy levels. Crucially, there is no further
accumulation of GSH in those cells already replete in GSH, rendering
NAC ineffectual once GSH has been replenished.
In light of these issues, NAC should not be considered a powerful an-
tioxidant, nor should it be seen as a panacea in all conditions driven by
oxidative stress. However, there is a significant opportunity for a strati-
fied approach to NAC therapy in a wide range of conditions, using intra-
cellular GSH as the predictor of efficacy. This approach is likely to be
most successful in conditions where target cells are easily accessible
for GSH measurement (e.g. platelets for anti-thrombotic therapy,
T-cells for HIV treatment, monocytes and neutrophils for certain anti-
inflammatory therapy), but there is the potential for GSH in these cells
to also act as surrogate markers for systemic GSH depletion that might
be relevant in some other conditions. Overall, researchers should
not be discouraged by some of the recent negative findings for NAC in
novel indications. Instead, we should take heart from the monumental
success of NAC in acetaminophen overdose therapy and seek similar op-
portunities where GSH depletion is a key component in the disease
aetiology. Only in these situations is NAC therapy likely to represent a
credible therapeutic solution.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Author declaration
The authors declare that this manuscript has not been published or
submitted for publication to any other journals.
157
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