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J. Biol. Chem., Vol. 276, Issue 52, 48967-48972, December 28, 2001
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From the Department of Chemistry and Biochemistry, University of
South Carolina, Columbia, South Carolina 29208
Received for publication, August 24, 2001, and in revised form, October 18, 2001
The advanced glycation end-product (AGE)
hypothesis proposes that accelerated chemical modification of proteins
by glucose during hyperglycemia contributes to the pathogenesis of
diabetic complications. The two most commonly measured AGEs,
N The Maillard or browning reaction between sugars and proteins
leads to the formation of chemical modifications and cross-links in
proteins, known as advanced glycation end-products
(AGEs)1 (1). These products
contribute to the age-dependent chemical modification of
long lived tissue proteins (2), and accelerated formation of AGEs
during hyperglycemia is implicated in the development of diabetic
complications (1, 2). Consistent with the AGE hypothesis, AGE
inhibitors, such as aminoguanidine (AG) (3) and pyridoxamine (PM) (4),
inhibit the formation of AGEs in various proteins in vitro
and in collagen in vivo (5, 6) and retard the development of
diabetic complications in animal models. The two most commonly measured
AGEs, N Reagents--
Unless otherwise noted, all chemicals were
purchased from Sigma/Aldrich Chemical Co. Monobasic and dibasic sodium
phosphate salts were purchased from EM Science (Gibbstown, NJ);
heptafluorobutyric acid (HFBA) from Acros (Pittsburgh, PA), and nitric
acid and HPLC grade acetonitrile from Fisher Scientific (Pittsburgh,
PA). Tenilsetam ((±)-3-(2-thienyl)-2-piperazinone) (9, 10) was a gift
from Aventis Pharma, Germany, and OPB-9195
((±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide) (11,
12) from Otsuka Pharmaceuticals, Japan. Phenacylthiazolium bromide
(PTB) and phenacyldimethylthiazolium bromide (PMTB) were synthesized
according to the methods of Vasan et al. (13) and Wolfenbüttel et al. (14), respectively, and purified
to homogeneity by reverse-phase HPLC. 2,3-Diaminophenzine (DAP) was
synthesized according to Soulis et al. (15). PTB, PMTB, and
DAP were homogeneous by reverse phase-HPLC analysis and by electrospray
ionization liquid chromatography-mass spectrometry. All water used in
these experiments was distilled and then deionized (15-18 M Measurement of the Kinetics of Oxidation of Ascorbic
Acid--
All incubations (1.5-ml total volume) were conducted in
chelex-treated 50 mM phosphate buffer, pH 7.4, in a water
bath at 30 °C; reagents were pre-equilibrated at this temperature
for at least 5 min. In preliminary experiments, the kinetics of
oxidation of AA was determined in quartz spectrophotometer cuvettes by
measuring the rate of decrease in absorbance at 265 nm, as described by Buettner (17); the cuvettes were precleaned by soaking overnight in 1%
nitric acid. AA (500 µM) was stable (>99% recovery) in
chelex-treated 50 mM phosphate buffer, pH 7.4, for at least
1 h. Addition of 500 nM CuCl2 yielded a
half-life of approximately 1 h.
For studies with AGE inhibitors, the copper and inhibitor were
preincubated in phosphate buffer for 5 min, and then the ascorbate was
added from a concentrated solution (75 µl of 10 mM AA in
water) to initiate the reaction. Aliquots (150 µl) were removed at 0, 15, 30, 45, and 60 min and transferred to autoinjector vials containing 15 µl of 10 mM diethylenetriaminepentaacetic acid (DTPA)
to quench the metal-catalyzed oxidation reaction. Samples were analyzed by RP-HPLC, using a Supelcosil LC-18 column (25 cm × 4.6 mm, 5 µm) (Supelco; Bellefonte, PA) on a Shimadzu (Columbia, MD) LC-10Ai liquid chromatograph equipped with a SIL-10Ai auto-injector and an
SPD-10AV UV-Vis detector. Solvents for HPLC were: A, 0.1% HFBA in
water and B, 50% acetonitrile. The gradient was 100% A at 0 min,
increase to 80% B from 0 to 4 min, return to 100% A from 4 to 4.1 min, then re-equilibrate in 100% A from 4.1 to 9 min. The absorbance
of ascorbic acid was measured at 244 nm (Fig. 1), and the peak area was
integrated to estimate the percent of AA remaining versus
time. The equations for the least-squares fits to these plots
(triplicate analyses) were determined with SigmaPlot 2000 (Jandel
Scientific) and used to determine the concentration of each compound
that inhibited the rate of AA oxidation by 50% (IC50).
All assays with AGE inhibitors were performed in triplicate by
HPLC, measuring residual ascorbate by absorbance at 244 nm (Fig.
1). None of the compounds tested
co-eluted with or otherwise interfered with the measurement of
ascorbate by this RP-HPLC method. In preliminary studies, we adjusted
experimental conditions to obtain a concentration of cupric ion that
would catalyze the oxidation of AA (500 µM) with an
approximate half-life of 1 h. As shown in Fig.
2 (lower lines; without AG or
PM), this was achieved by addition of 500 nM
CuCl2 to 50 mM chelex-treated phosphate buffer, pH 7.4, at 30 °C. This half-life was comparable with the half-life of ascorbate in 0.1 M phosphate buffers prepared in our
laboratory; however, buffers prepared with different batches of
phosphate salts varied in their catalytic activity because of
batch-to-batch variation in metal ion content.
The AGE inhibitors, AG and PM, inhibited the oxidation of AA in a
concentration-dependent manner (Fig. 2). The linearity of the semilogarithmic plots illustrates that the AGE inhibitors did not
alter the pseudo-first order kinetics of the autoxidation reaction.
Graphical analysis of the rate of ascorbate oxidation versus
inhibitor concentration indicated that percent inhibition was not a
linear function of inhibitor concentration. The linear relationships
between percent inhibition and the square of the inhibitor
concentration, shown in Fig. 3, were
consistent with formation of 2:1 or higher valency complexes between AG
or PM and Cu(II) ions. These data yielded IC50 values of
~2.5 mM for AG and ~1 mM for PM. Amine
nitrogens are common ligands for transition metal ions and pyridoxine
(IC50 ~3.6 mM) and pyridoxal
(IC50
Chelating Activity of Advanced Glycation End-product
Inhibitors*
ABSTRACT
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-(carboxymethyl)lysine and pentosidine, are
glycoxidation products, formed from glucose by sequential glycation and
autoxidation reactions. Although several compounds have been developed
as AGE inhibitors and are being tested in animal models of diabetes and
in clinical trials, the mechanism of action of these inhibitors is
poorly understood. In general, they are thought to function as
nucleophilic traps for reactive carbonyl intermediates in the formation
of AGEs; however alternative mechanisms of actions, such as chelation, have not been rigorously examined. To distinguish between the carbonyl
trapping and antioxidant activity of AGE inhibitors, we have measured
the chelating activity of the inhibitors by determining the
concentration required for 50% inhibition of the rate of
copper-catalyzed autoxidation of ascorbic acid in phosphate buffer. All
AGE inhibitors studied were chelators of copper, as measured by
inhibition of metal-catalyzed autoxidation of ascorbate. Apparent
binding constants for copper ranged from ~2 mM for
aminoguanidine and pyridoxamine, to 10-100 µM for
carnosine, phenazinediamine, OPB-9195 and tenilsetam. The AGE-breakers,
phenacylthiazolium and phenacyldimethylthiazolium bromide, and their
hydrolysis products, were among the most potent inhibitors of ascorbate
oxidation. We conclude that, at millimolar concentrations of AGE
inhibitors used in many in vitro studies, inhibition of AGE
formation results primarily from the chelating or antioxidant activity
of the AGE inhibitors, rather than their carbonyl trapping activity.
Further, at therapeutic concentrations, the chelating activity of
AGE inhibitors and AGE-breakers may contribute to their inhibition of
AGE formation and protection against development of diabetic complications.
INTRODUCTION
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MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
-(carboxymethyl)lysine (CML) and pentosidine, are
glycoxidation products formed by sequential glycation and oxidation
reactions (7), and traces of transition metal ions in physiological
buffers are potent catalysts of the formation of these AGEs in
vitro (8). AGE inhibitors are nucleophilic compounds designed to
trap reactive carbonyl or dicarbonyl intermediates in AGE formation.
However, as shown here, some of these compounds also have potent
chelating activity, making it difficult to dissect the antioxidative,
chelating activity from the carbonyl trapping activity of the
inhibitors in in vitro studies. In the present work, we
measured the chelating activity of AGE inhibitors by determining the
concentration required for 50% inhibition of copper-catalyzed
autoxidation of ascorbic acid in phosphate buffer. Using this assay, we
show that AGE inhibitors have weak-to-potent metal chelating activity,
and that, in fact, many experiments demonstrating the activity of AGE
inhibitors in vitro are likely to be measuring the chelating
activity rather than carbonyl trapping activity of these compounds. We
also show that AGE-breakers and their hydrolysis products are potent
chelators of copper and conclude that both the carbonyl trapping and
chelation activity of AGE inhibitors and AGE-breakers may be involved
in their therapeutic mechanism of action.
MATERIALS AND METHODS
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) using a mixed bed ion-exchanger with activated charcoal polisher. Chelex-100 (~80% water content) was suspended and allowed to settle several times in water to remove soluble chelator and fine particles (16). To
remove metal ions from phosphate buffer, chelex-100 resin (7 g/liter,
wet weight) was added to 50 mM phosphate buffer, pH 7.4, in
a 2-liter plastic container and rocked gently overnight at room
temperature. The buffer was stored at room temperature in the same
container, allowing the resin to settle to the bottom; aliquots were
removed for experiments, as needed.
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View larger version (17K):
[in a new window]
Fig. 1.
Typical data obtained from RP-HPLC analyses
of the kinetics of oxidation of ascorbate. These data were
obtained for a reaction mixture containing 500 µM AA and
500 nM CuCl2.
View larger version (25K):
[in a new window]
Fig. 2.
Kinetics of oxidation of ascorbate in the
absence and presence of various concentrations of aminoguanidine
(A) and pyridoxamine (B).
Reaction mixtures contained 500 µM AA, 500 nM
CuCl2, and various concentrations of AG and PM. Data points
represent means ± S.D. of triplicate experiments.
5 mM), with a hydroxymethyl or
carboxaldehyde group, in lieu of the aminomethyl group of PM, were less
inhibitory than PM itself (Fig. 3).
View larger version (19K):
[in a new window]
Fig. 3.
Effect of aminoguanidine and B6
vitamer concentration on the kinetics of copper-catalyzed oxidation of
ascorbic acid. Data for AG and PM are from Fig. 2. Inhibition is
plotted as a function of the square root of the concentration of AGE
inhibitor. Dashed horizontal lines in this and later figures
indicate 50% loss of ascorbic acid
Carnosine and its the constituent amino acid histidine were potent
inhibitors of AA oxidation, with IC50 values ~4 and 12 µM, respectively (Fig.
4A). The antioxidative effect
of carnosine and histidine was an asymptotic function of increasing
inhibitor concentration, suggesting that the chelate species may have
some residual catalytic activity. Among other compounds tested, taurine and ethanol had no effect on metal-catalyzed oxidation of AA. As shown
in Fig. 4B, the AGE inhibitors, DAP and tenilsetam, had IC50 values of ~50 and 25 µM, respectively,
whereas OPB-9195 (Fig. 4C) yielded a consistently non-linear
response with a minimum at ~5 µM.
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Both of the AGE-breakers, PTB and PMTB, were also potent inhibitors of
ascorbate oxidation, with IC50 values of ~10 and 80 µM, respectively (Fig. 5).
Because the half-life of PTB and PMTB were 2 and 8 h,
respectively, in phosphate buffer at
30 °C,2 we also measured
the activity of the hydrolysis products in the ascorbate oxidation
system. For these experiments, the AGE-breakers were incubated for
24 h in buffer prior to addition of the ascorbate. As also shown
in Fig. 5, the hydrolysis products had IC50 values of <2
µM and were among the most potent inhibitors of
metal-catalyzed oxidation of ascorbate. The non-linear response
obtained with native PTB (Fig. 5A) suggests that ongoing
hydrolysis, ~30% during the course of the 1-h incubation, may have
contributed to the increased inhibitory activity of this compound
at higher concentrations.
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) and PTB hydrolysis products (
)
generated by incubation in phosphate buffer for 24 h.
B, PMTB (
) and PMTB hydrolysis products (
) generated
by incubation in phosphate buffer for 24 h.
To assess the potential role of AGE inhibitors and AGE-breakers as
inhibitors of metal-catalyzed oxidation chemistry in vivo, we also measured the effects of plasma albumin on the kinetics of
ascorbate oxidation. As shown in Fig. 6,
among all the compounds tested, bovine serum albumin was the most
potent inhibitor of ascorbate oxidation on a molar basis. The
IC50 for bovine serum albumin, ~80 nM (~5
µg/ml), was 16% of the concentration of Cu(II) in the reaction
system, suggesting at least 6 binding sites for copper.
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Chelation Activity of AGE Inhibitors--
The late Simon Wolff was
a pioneer in focusing attention on the metal chelating activity of
drugs designed for other activities (18, 19). Aldose reductase
inhibitors and anti-inflammatory agents with anticataract activity were
shown to have substantial chelating activity, suggesting that their
chelating activity might protect lens proteins from chemical damage by
inhibiting metal-catalyzed autoxidation of sugars or ascorbate (20,
21). In the present study we have evaluated the chelating activity of
various AGE inhibitors to determine the role of metal chelation in the
mechanism of action of AGE inhibitors. A typical reaction pathway for
the formation of AGEs from AA (and other carbohydrates) in
vitro is shown in Fig. 7.
Metal-catalyzed autoxidation chemistry accelerates the browning and
cross-linking of protein by carbohydrates and is essential for the
formation of the glycoxidation products, CML and pentosidine. Chelators
such as DTPA are potent inhibitors of formation of these AGEs from
ascorbate (22) and glucose (23) (Fig. 7, dotted arrows). In
contrast, AGE inhibitors, such as AG and PM, are thought to function as
carbonyl traps (3, 4), reacting with electrophilic, carbonyl
intermediates formed on autoxidation of carbohydrates, thereby
protecting against chemical modification of nucleophilic residues on
protein (Fig. 7, solid arrow). Our experiments show,
however, that AGE inhibitors are also transition metal chelators and
inhibit the autoxidation of ascorbate, prior to formation of reactive
carbonyl compounds. AGE inhibitors had IC50 values for
copper ranging from the millimolar range for AG and PM to micromolar
values for carnosine, tenilsetam, DAP, and OPB-9195. These results
indicate that AGE inhibitors have two mechanisms of action in
vitro: first, inhibition of formation of reactive carbonyl
intermediates; and second, nucleophilic reaction with these
intermediates.
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AGE Inhibitors in Vitro-- High concentrations of AG and other inhibitors have been employed in many studies, including our own (23-26), on the mechanism of action of AGE inhibitors. These high inhibitor concentrations have been justified because of the high concentrations of glucose used to accelerate AGE formation in in vitro reactions. Based on the present work, however, it is more likely that AG, at concentrations in the 5-25 mM range, i.e. 2-10-fold higher than its IC50, exerts its primary effect by inhibiting autoxidation chemistry; this inhibition is observed not only with the copper-supplemented chelex-treated phosphate buffers used in our experiments, but also with commercial phosphate buffers containing traces of mixed metal ions. Similar results were obtained for AG and PM in the presence of iron salts, although iron was about 10-fold less effective as a catalyst of ascorbate autoxidation reactions at neutral pH. Other AGE inhibitors, such as carnosine, DAP, tenilsetam, and OPB-9195, which have much stronger metal binding activity (Table I), are likely to act primarily as chelators at the millimolar concentrations commonly employed for these reagents in vitro. Chelation may, therefore, confound the identification of AGE inhibitors, e.g. in two recent studies in which a large number of heterocyclic AGE inhibitors were described (27, 28) but are more likely to inhibit AGE formation through their chelation, rather than carbonyl trapping activity. For AG and PM, however, triazines (29) and amides (30) have been identified as discrete adducts to carbonyl compounds during glycoxidation and lipoxidation reactions, confirming that, in addition to their chelating activity, they also act as true scavengers of carbonyl compounds. Similar experiments will have to be performed with other AGE inhibitors to confirm their proposed mechanism of action as carbonyl traps.
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The estimate of the IC50 for inhibition of ascorbate oxidation is a useful, but comparative measure of the chelation activity of AGE inhibitors. It is the empirical result of equilibrium constants for metal binding by the multiple species of ascorbate (31), the AGE inhibitor and the phosphate buffer ions in solution, rather than an actual Kd for the AGE inhibitor-metal complex. In most cases, except for pyridoxamine (32) and carnosine (33), true metal binding constants have not been measured. Because of the complexity of the equilibria involved, the IC50 for an AGE inhibitor will vary with buffer, metal ion, and ascorbate concentration, and even with the specific sugar under study, e.g. glucose, which exists to a lesser extent in the enolate conformation, would bind transition metal ions more weakly than ascorbate. Variations in the species and concentrations of metal ion contaminants in buffers will also affect the apparent IC50 for specific inhibitors, depending on their respective binding constants with AGE inhibitors.
How can one avoid the complex and confounding effects of chelation in studies on AGE inhibitors? One solution is to conduct these studies in the presence of a strong chelator, such as DTPA, so that the contribution of the AGE inhibitor to chelation would be minimal. However, DTPA itself is a potent inhibitor (>99% at 1 mM (23)) of AGE formation from glucose and ascorbate, so that reaction times would be excessive, even at high glucose concentration. We suggest that it may be best to evaluate the efficacy of AGE inhibitors by studying the browning of proteins by pentoses. Pentoses are 10-100 times more reactive than glucose with protein, so that lower concentrations of sugar can be used. Glycation of protein by pentoses also leads to formation of AGEs, cross-links and fluorescence characteristic of the modification of protein by glucose (34). Importantly, Maillard reactions of pentoses proceed readily under nitrogen and in the presence of chelators (35). Experiments on the browning of proteins by pentoses can be conducted in the presence of strong chelator such as DTPA, so that the chelating activity of the inhibitor would not affect the kinetics of AGE formation in pentose model systems.
AGE Inhibitors in Vivo-- The significance of the chelating activity of AGE inhibitors in vivo is difficult to assess, considering the powerful inhibition of ascorbate oxidation observed with albumin (Fig. 6). Yet, albumin is subject to metal-catalyzed oxidation and formation of Maillard products from glucose in vitro, and AGEs are present on albumin in vivo (36). It is likely that metals bound to albumin are in equilibrium with metals bound to other proteins, and protein-bound metal ions, even when bound to proteins such as albumin (37) or low density lipoprotein (38), may remain redox-active and induce site-specific cleavage of the proteins in the presence of peroxide (39). Despite lower binding constants, compared with albumin and chelators such as DTPA, AGE inhibitors may gradually deplete excess chelatable iron in the body by promoting the excretion of metal ion complexes in urine. Even a weak chelator, such as AG or PM, which might not inhibit autoxidation reactions significantly at therapeutic concentrations (<100 µM), could promote the gradual removal of free metal ions from tissues and plasma for excretion in urine, decreasing overall metal-catalyzed oxidative damage to proteins in vivo. Monnier and Eaton and co-workers (40, 41) have proposed that AGEs on proteins may serve to bind redox-active, transition metal ions, enhancing local oxidative damage to proteins. If AGE inhibitors remove weakly bound metal ions from these "glycochelates," they may both inhibit AGE formation (by chelation and/or carbonyl trapping) and also reduce other metal-catalyzed oxidative damage to tissues resulting from the presence of AGEs. Measurements of chelatable iron and copper in control versus AGE inhibitor-treated animals should clarify the therapeutic significance of the weak chelating activity of AGE inhibitors. Notably, although chelators are not used clinically for the treatment of diabetic complications, chelators have recently proven effective in treatment of vascular disease (42) and neuropathy (43) in the STZ-diabetic rat.
AGE inhibitors vary widely in their IC50 values in the ascorbate model system, from the millimolar range for AG and PM, to the micromolar range for carnosine, DAP, tenilsetam, and OPB-9195. At plasma concentrations of <100 µM, i.e. <10% of their IC50, both AG and PM were effective in inhibiting the formation of AGEs and development of complications in animal models of diabetes (5). Among the stronger chelators, the concentration of carnosine in tissues (up to 20 mM) (44) far exceeds its IC50, while the therapeutic concentration of tenilsetam, ~10 µM (45), is comparable with its IC50 in the ascorbate system (25 µM; Fig. 4B). The therapeutic concentrations of DAP and OPB-9195 have not been reported, but are probably also in the micromolar range, suggesting that chelation would contribute to their AGE inhibitory activity in vivo.
Chelating Activity of AGE-breakers-- The AGE-breakers PTB and PMTB were among the most potent inhibitors of copper-catalyzed oxidation of ascorbate, and the hydrolysis products of these compounds exhibited even stronger chelating activity. Hydrolysis of PTB leads to opening of the thiazolium ring, producing a sulfhydryl compound (46). Mercaptans are excellent ligands for copper and other transition metals, which might explain the strong chelating activity of the hydrolysis products of PTB and PMTB. Because PTB also protects Escherichia coli against MGO toxicity, almost as well as AG (47), it is also possible that the hydrolysis products may have carbonyl trapping activity. The chelating properties of AGE-breakers is sufficiently strong that they may also have some lathyrogenic activity, inhibiting the enzymatic cross-linking of collagen, possibly leading to decreased cross-linking and greater elasticity of newly synthesized collagen.
Summary--
We have shown that AGE inhibitors have significant
copper chelating activity. While we have not studied other metals in
detail, similar inhibitory effects were observable with phosphate
buffers containing a mixture of trace metal ions. The general metal
chelating activity of AGE-directed drugs containing nitrogen and thiol
groups most certainly contributes to the chelating activity of putative AGE inhibitors in vitro and could be important in their
mechanism of action in vivo. Screening assays for AGE
inhibition should account for metal chelation by working with inhibitor
concentrations below their IC50 or by using pentoses as
glycating agents. Identification and characterization of products
trapped by the AGE inhibitors is also critical for confirming their
mechanism of action. Defining the chelating versus carbonyl
trapping activity of AGE inhibitors is essential for understanding the
mechanism of action of these drugs and the possible benefits of
chelation therapy in diabetes, and for developing more effective,
clinically useful inhibitors of diabetic complications.
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ACKNOWLEDGEMENT |
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We thank Shengzu Yang, University of South Carolina, for the synthesis of phenacylthiazolium bromide and phenacyldimethylthiazolium bromides.
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FOOTNOTES |
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* This work was supported by Research Grant DK-19971 from the NIDDKD, National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Chemistry and
Biochemistry, University of South Carolina, Columbia, SC 29208. Tel./Fax: 803-777-7272; E-mail: baynes@mail.chem.sc.edu.
Published, JBC Papers in Press, October 24, 2001, DOI 10.1074/jbc.M108196200
2 S. R. Thorpe, J. E. Litchfield, S.-Z. Yang, and J. W. Baynes, manuscript in preparation.
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ABBREVIATIONS |
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The abbreviations used are:
AGE, advanced glycation end-product;
AA, ascorbic acid;
AG, aminoguanidine;
CML, N-(carboxymethyl)lysine;
DAP, diaminophenazine;
DTPA, diethylenetriaminepentaacetic acid;
HFBA, heptafluorobutyric
acid;
PM, pyridoxamine;
PMTB, phenacyldimethylthiazolium bromide;
PTB, phenacylthiazolium bromide;
RP-HPLC, reverse phase-high performance
liquid chromatography.
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REFERENCES |
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