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Special article
Erythritol is a sweet antioxidant 
Gertjan J.M. den Hartog, Ph.D.
,
*, Agnes W. Boots, Ph.D.
, Aline Adam-Perrot, Ph.D.
b,
y
,Fred Brouns, Ph.D.
c
, Inge W.C.M. Verkooijen, M.Sc.
d
, Antje R. Weseler, Ph.D.
,Guido R.M.M. Haenen, Ph.D.
, and Aalt Bast, Ph.D.
 Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
b
Cargill R&D Center Europe, Vilvoorde, Belgium
c
 Department of Human Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
d
Clinical Trial Center Maastricht, Maastricht, The Netherlands
Manuscript received November 21, 2008; accepted May 13, 2009.
Abstract Objective:
Hyperglycemia, oxidative stress, and the onset and progression of diabetic complicationsare stronglylinked. Reduction of oxidativestress could beof utmost importance in thelong-term treat-ment of diabetic patients. The chronic nature of the disease calls for a mode of antioxidant intake that can be sustained easily, e.g., by the diet. Erythritol, a simple polyol, could be such a compound. It isorally available, well tolerated, and its chemical structure resembles that of mannitol, a well-knownhydroxyl radical (HO
) scavenger.
Methods:
We studied the antioxidant properties of erythritol in vitro and subsequently determined itsantioxidant activity and its vasoprotective effect in the streptozotocin diabetic rat.
Results:
Erythritol was shown to be an excellent HO
radical scavenger and an inhibitor of 2,2
0
-azo-bis-2-amidinopropanedihydrochloride–inducedhemolysisbutinerttowardsuperoxideradicals.High-performanceliquidchromatographicandelectronspinresonancespectroscopystudiesshowedthatthereaction of erythritol with hydroxyl radicals resulted in the formation of erythrose and erythrulose byabstractionofacarbon-boundhydrogenatom.Inthestreptozotocindiabeticrat,erythritoldisplayedanendothelium-protective effect and, in accordance with the in vitro experiments, erythrose was found inthe urine of erythritol-consuming rats.
Conclusion:
Erythritol acts as an antioxidant in vivo and may help protect against hyperglycemia-induced vascular damage.
Ó
2010 Elsevier Inc. All rights reserved.
 Keywords:
Erythritol; Diabetes; Oxidative stress; Rat 
Introduction
Diabetes mellitus (DM) is a chronic disease with a rapidlyincreasingprevalencecharacterizedbyhyperglycemia.Itisas-sociatedwithahighriskofvascular,renal,neuronal,andocular damage. Patients with DM often develop diabetic complica-tions including myocardial infarction, stroke, blindness, andgangrene[1]. A large body of evidence indicates that these di-abetic complications are linkedto oxidative stress[2]. There isconsiderable evidence that hyperglycemia causes formation of oxygenradicals(mostnotablythehydroxylradical[HO
])andlowers antioxidant defenses[3]. Reducing hyperglycemia byreplacing sucrose with sweeteners will probably reduce theamount of oxidative stress. The remaining oxidative damagecanbepreventedbysupplementingwithantioxidants.Prevent-ing hyperglycemia and supplying appropriate levels of antiox-idants seems a rational approach to reduce the amount of oxidative damage and thus the onset and development of dia-betic complications in patients with DM[4]. Because of thechronic nature of the disease, supplementation with antioxi-dants also has to be long term. Intake of appropriate levels of antioxidants with food or drink would be an acceptable proce-dureandeasyforthe patient.Basedonitsmolecularcharacter-istics, erythritol may be a good antioxidant to incorporate infood and beverage formulations. However, its antioxidant properties have thus far not been studied in detail. Erythritol
y
Current address: Tate & Lyle Ingredients France, Villeneuve d’Ascq,France.*Correspondingauthor. Tel.:
þ
31-43-388-2916; fax:
þ
31-43-388-4149.
 E-mailaddress:
gj.denhartog@farmaco.unimaas.nl(G.J.M. denHartog).0899-9007/10/$ – see front matter 
Ó
2010 Elsevier Inc. All rights reserved.doi:10.1016/j.nut.2009.05.004Nutrition 26 (2010) 449–458www.nutritionjrnl.com
 
isasimplepolyol(1,2,3,4-butanetetrol),presentinsmallquan-tities in melons and peaches, and currently produced in largequantities for use as a low-calorie, tooth-friendly bulk sweet-ener [5].Extensivetoxicologictestinghasshownthaterythritolis well tolerated and has no toxic effects, even after consump-tion of large quantities[6,7]. In addition, it has no impact onblood insulin or glucose levels, which renders it a useful andsafe food component for patients with DM. A compound that closely resembles erythritol is the therapeutically applied pol-yolmannitol,awell-knownHO
radicalscavenge[8,9].How-ever, in contrast to mannitol, of which about 75% remainsunabsorbed, erythritol is rapidly and virtually completely (upto 90%) absorbed from the gut [10], which makes it easy toreach appropriate systemic concentrations required to neutral-ize the highly reactive HO
radicals.The goal of the present study was to evaluate the antioxi-dant properties of erythritol in vitro and subsequently studyits potential protective effect in vivo in the streptozotocin-in-duced diabetic rat.
Materials and methods
 Hydroxyl radical scavenging
The rate constants for the reaction with HO
radicals of erythritol and related polyols were determined according toHalliwell et al.[11]. Erythritol and other polyols (xylitol, sor-bitol, and mannitol) were tested in concentrations rangingfrom 0 to 8 mM.
Superoxide radical scavenging
ThesuperoxideradicalscavengingactivityoferythritolwasdeterminedaccordingtoKirkovaetal.[12]usingnitrobluetet-razolium (NBT; 50
m
M) as detector for superoxide radicalsgenerated by xanthine 0.1 mM and xanthine oxidase 10 mU/ mL. Possible interference by inhibition of xanthine oxidaseby the test compounds was checked by measuring the rate of uric acid formation spectrophotometrically at 293 nm.
 Hemolysis assay
To determine the antioxidant activity of erythritol, itseffect on 2,2
0
-azobis-2-amidinopropane dihydrochloride– induced hemolysis was investigated according to Vostersand Ne`ve[13]. In short, a red blood cell suspension was in-cubated with erythritol (0–50 mM) for 5 min at 37
C after which 2,2
0
-azobis-2-amidinopropane dihydrochloride(50 mM) was added. At regular intervals (0–300 min), 200-
m
L aliquots were taken and diluted in 2 mL of 0.9% NaCl so-lution. The extent of hemolysis was determined by treatingthe sample with Hemoglobina TC (potassium hexacyanofer-rate [III] 2.4 mM, potassium cyanide 3 mM) for hemoglobindetermination. The absorbance of the mixture was measuredat 540 nm. One hundred percent hemolysis was obtained byadding a200-
m
Laliquot to2 mL ofdemineralized water.Thepercentage of hemolysis was calculated from the ratio of hemolysis in the test sample to 100% hemolysis. The timeneeded to obtain 50% hemolysis was determined for eachconcentration by fitting the data with the three-parameter sig-moid model from SigmaPlot 2001 for Windows (SPSS Inc.,Chicago, IL, USA).
 Electron paramagnetic resonance spectroscopy
The formation of radical intermediates during scavengingof hydroxyl radicals by erythritol was studied with an elec-tron spin resonance spectrometer (EMX, Bruker GmbH,Karlsruhe, Germany) with 5,5
0
-dimethyl pyrroline N-oxide(DMPO) as a spin trap. The spectrometer settings were:power, 20 mW; center field, 3488 G; modulation amplitude,0.5 G; time constant, 20.48 ms.
 Identification of oxidation products
Erythritol (100 mM) was treated with a Fenton reagent (10 mM H
2
O
2
, 1 mM Fe[II]SO
4
, and 1.04 mM ethylenedia-minetetra-aceticacid)for30 min.Analysisofoxidationprod-ucts was carried out according to Nascimento et al.[14]. Inshort, samples were treated with 2,4-dinitrophenylhydrazine(2.5 mM) in the presence of perchloric acid to form the 2,4-dinitrophenylhydrazones of any present carbonyl compound.After60 minofshakingatroom temperaturethesolutionwasanalyzed by high-performance liquid chromatography(column Hypersil (Supelco Inc., Bellefonte, PA, USA)5
m
m, eluent 25:75 acetonitrile:0.1% trifluoroacetic acid,detection at 365 nm).The identity of the reaction products was determined bycomparing their retention times with those for pure erythrose(2,3,4-trihydroxybutanal) and erythrulose (1,3,4-trihydroxy-2-butanone) that underwent the same derivation procedure.
 Antioxidant activity of erythritol in the streptozotocin-induced diabetic rat 
The study protocol was approved by the ethics committeefor animals of the Universiteit Maastricht. Twenty rats (Wis-tar, 10 male, 10 female, 200–250 g of body weight) weresupplied by Charles River Nederland BV (Maastricht, Neth-erlands) and kept under standard conditions. Standard food(Ssniff Spezialdia¨ten GmbH, Soest, Germany) and acidifieddrinking were provided ad libitum. The study’s protocolwas approved by the ethics committee for animals of theUniversiteit Maastricht.
 Induction of DM 
Diabetes mellitus was induced according to the method of Hasselbaink et al.[15]. The rats were anaesthetized with hal-othane and subsequently treated with 70 mg/kg of streptozo-tocin in citrate buffer (100 mM, pH 4.5) by intravenousinjection in the tail vein. Controls received citrate buffer 
G. J. M. den Hartog et al. / Nutrition 26 (2010) 449–458
450
 
only. After 7 d, blood glucose was determined with a glucosemeter (Lifescan BV, Maastricht, Netherlands).The 10diabeticrats were dividedin twogroups: those that received normal drinking water (group D,
n
¼
5) and thosethat received erythritol-supplemented water (group DE,
n
¼
5) for 21 d. The 10 non-diabetic rats were also dividedin two groups: normoglycemic rats that received normaldrinking water (group N,
n
¼
5) and those that receivederythritol-supplemented water (group NE,
n
¼
5) for 21 d.The amount of solution consumed by each rat was moni-tored. The concentration of the erythritol solution was read- justed daily to ensure that each rat had a daily consumptionof 1000 mg of erythritol per kilogram of body weight.Weight and blood glucose levels of the rats were determinedweekly.
 Ex vivo aortic reactivity measurements
After sacrificing the rats, with CO
2
 /O
2
blood was rapidlycollected by venipuncture. The thoracic parts of the aortaswere excised. These were immediately placed in Krebs-Ringer buffer (NaCl 118 mM, KCl 4.4 mM, CaCl
2
2.5 mM, KH
2
PO
4
1.2 mM, MgSO
4
1.2 mM, glucose10 mM, and NaHCO
3
25 mM) after which excess fat andconnective tissue were removed. Rings approximately4 mm in length were cut and mounted between stainless steelhooks in a 20-mL organ bath filled with Krebs-Ringer buffer,keptat37
C,andbubbledwith95%O
2
 /5%CO
2
.Anisomet-ric force transducer (Grass FT03, West Warwick, RI, USA)was attached to each strip, after which the resting tensionwas constantly readjusted to 1.0
3
g
for 60 min. Integrityof the tissues was checked with phenylephrine (10
m
M) andcarbachol (100
m
M), followed by a washout period of 30 min. The aortic rings were then submaximally contractedwith phenylephrine (10
m
M). When a stable contraction wasestablished, a carbachol concentration–response curve(10 nM to 100
m
M) was recorded. When a stable relaxationwas obtained after the last addition of carbachol, sodiumnitroprusside (SNP; 100
m
M) was added to the organ bathto induce maximum relaxation.ThepD
2
[negativelogarithm oftheconcentration thatpro-duces 50% of the maximal response (EC
50
)] values and max-imum effect of carbachol were obtained by fitting the data (four-parameter logistic curve, SigmaPlot 2001 for Win-dows, SPSS Inc., Chicago, IL, USA). Total relaxation (relax-ationbycarbacholandSNP)and theSNP fraction (partofthetotal relaxation caused by SNP) were calculated from thedata.
 Blood antioxidant and oxidative stress parameters
Erythrocyte glutathione (GSH) and glutathione disulfide(GSSG) were determined according to Baker et al.[16]with the modifications of Vandeputte et al.[17]. The troloxequivalent antioxidant capacity (TEAC) was determined indeproteinized plasma according to Arts et al.[18].Thiobarbituric acid-reactive substances (TBARS) were mea-sured in plasma according to Lepage et al.[19].
Chemicals
Erythritol, xylitol, sorbitol, and mannitol were providedby Cargill (Vilvoorde, Belgium). Dinitrophenylhydrazine(DNPH) and high-performance liquid chromatographic elu-ents were purchased from Fluka GmbH (Fluka ChemieGmbH, Buchs, Switzerland) and recrystallized from acetoni-trile before use. Streptozotocin was purchased from Sigma Chemical Co. (St. Louis, MO, USA). All other chemicalswere of reagent grade.
Statistical evaluation
The data are expressed as mean
6
standard error. Differ-ences between groups were investigated with Student’s
test and those with a 
P
value
<
0.05 were considered statisticallysignificant.
Results
 Hydroxyl and superoxide radical scavenging properties of erythritol and related polyols
Figure 1presents the effects of erythritol, xylitol, sorbitol,and mannitol on hydroxyl radical–induced deoxyribose deg-radation. Erythritol scavenged HO
radicals with a rate con-stant of 1.18
3
10
9
M/s. In comparison, xylitol, sorbitol, and
Concentration (mM)
0 2 4 6 8 10
   1   /   A
   5   3   2
0.60.81.01.21.41.61.82.02.2MannitolSorbitolXylitolErythritol
Number of hydroxyl groups
4 5 6
   k
   S
   (  x   1   0
   9
   M
  -   1  s  -   1
   )
1.01.21.41.6
Fig. 1. Effect of test compounds on the HO
radical-induced degradation of 2-deoxyribose. Values are means of three experiments. SEMs for A
532
wereapproximately 2% of the measured value; error bars have been omitted for clarity. Fitting using linear regression (least squares method) was performedusing SigmaPlot 4.01 for Windows (SPSS Inc., Chicago, IL, USA). (Inset)Correlation between the rate constant for HO
radical scavenging and thenumber of hydroxyl groups present in the tested polyols. A
532
; absorbanceat a wavelength of 532 nm.
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451
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