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J Am Soc Nephrol 11:1719-1725, 2000
© 2000 American Society of Nephrology

Mechanism of the Inhibitory Effect of OPB-9195 [(±)-2-Isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide] on Advanced Glycation End Product and Advanced Lipoxidation End Product Formation

TOSHIO MIYATA*, YASUHIKO UEDA*, KOICHI ASAHI*, YUKO IZUHARA*, REIKO INAGI*, AKIRA SAITO*, CHARLES VAN YPERSELE DE STRIHOU{dagger} and KIYOSHI KUROKAWA*

* Molecular and Cellular Nephrology, Institute of Medical Sciences and Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
{dagger} Service de Nephrologie, Université Catholique de Louvain, Brussels, Belgium.

Correspondence to Dr. Toshio Miyata, Molecular and Cellular Nephrology, Institute of Medical Sciences and Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1143, Japan. Phone: 81-463-93-1936; Fax: 81-463-93-1938; E-mail: t-miyata{at}is.icc.u-tokai.ac.jp


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Abstract. The accumulation in uremic plasma of reactive carbonyl compounds (RCO) derived from both carbohydrates and lipids ("carbonyl stress") contributes to uremic toxicity by accelerating the advanced glycation and lipoxidation of proteins. It was previously demonstrated that OPB-9195 [(±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide] inhibited the in vitro formation of advanced glycation end products (AGE) in uremic plasma. This study was designed to elucidate the mechanism of action of OPB-9195 by further delineating the AGE and advanced lipoxidation end product (ALE) precursors targeted by this drug. The inhibitory effects of OPB-9195 on the formation of two AGE (N{epsilon}-carboxymethyllysine and pentosidine) on bovine serum albumin incubated with various AGE precursors were examined. Inhibition of N{epsilon}-carboxymethyllysine and pentosidine formation with OPB-9195 was more efficient than with aminoguanidine. OPB-9195 also proved effective in blocking the carbonyl amine chemical processes involved in the formation of two ALE (malondial-dehyde-lysine and 4-hydroxynonenal-protein adduct). The efficiency of OPB-9195 was similar to that of aminoguanidine. When glucose-based peritoneal dialysis fluid was incubated in the presence of OPB-9195, a similar inhibition of AGE formation was observed. The direct effect of OPB-9195 on major glucose-derived RCO in peritoneal dialysis fluids was then evaluated. The effects of OPB-9195 could be accounted for by its ability to trap RCO. The concentrations of three major glucose-derived RCO (glyoxal, methylglyoxal, and 3-deoxy-glucosone) were significantly lower in the presence of OPB-9195 than in its absence. Aminoguanidine had a similar effect. In conclusion, OPB-9195 inhibits both AGE and ALE formation, probably through its ability to trap RCO. OPB-9195 might prove to be a useful tool to inhibit some of the effects of RCO-related uremic toxicity.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Recent studies by our group and other groups have demonstrated the accumulation in uremic plasma of reactive carbonyl compounds (RCO) derived from both carbohydrates and lipids ("carbonyl stress") (1,2,3,4). These RCO react nonenzymatically with proteins and form advanced glycation end products (AGE) and advanced lipoxidation end products (ALE) (4). Their deleterious effects have been suggested as the pathologic basis of complications associated with chronic renal failure and long-term dialysis, such as dialysis-related amyloidosis, atherosclerosis, and peritoneal membrane failure (4,5,6,7,8). Prevention of the effects of RCO on advanced glycation or lipoxidation of proteins has thus become an important area of clinically relevant research.

We previously demonstrated that OPB-9195 [(±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide] (9) reduced the generation of pentosidine, which is used as a surrogate marker for AGE, in both uremic and normal plasma incubated in vitro (1). However, the AGE precursors targeted by OPB-9195 in uremic plasma remain to be identified.

Further studies demonstrated that OPB-9195 corrects, at least in part, several deleterious biologic effects of RCO in vitro and in vivo. In murine thymocytes and fibroblasts, it inhibits the phosphorylation of tyrosine residues of a number of intracellular proteins induced by the RCO glyoxal (GO) (10). When administered to Otsuka-Long-Evans-Tokushima fatty rats (a model of non-insulin-dependent diabetes mellitus), OPB-9195 reduces urinary albumin excretion and improves the morphologic features of glomeruli (9). Finally, oral administration of OPB-9195 to rats, after balloon injury of their carotid arteries, effectively reduces neointimal proliferation in arterial walls, which is an early and major step in the development of atherosclerotic lesions (11). The mechanism of action of OPB-9195 has yet to be fully described.

In this study, we take advantage of a previously described in vitro assay in which specific RCO-derived AGE and ALE are formed on bovine serum albumin (BSA) incubated with various precursors. We demonstrate that OPB-9195 is able to inhibit the formation of two AGE (N{epsilon}-carboxymethyllysine [CML] and pentosidine) from a variety of individual precursors, such as ribose, glucose, and ascorbate, as well as the formation of two ALE (malondialdehyde [MDA]-lysine and 4-hydroxynonenal [HNE]-protein adduct) from arachidonate. We rely on the same assay to demonstrate that OPB-9195 also inhibits AGE formation from commercial glucose-based peritoneal dialysis (PD) fluid containing several RCO, such as GO, methylglyoxal (MGO), and 3-deoxyglucosone (3-DG), all of which are generated from glucose during heat sterilization. Taken together, these results suggest that OPB-9195 reduces AGE and ALE formation by trapping RCO. The latter finding may prove relevant to current efforts to prevent the progressive deterioration of the peritoneal membrane during long-term PD.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
In Vitro Incubation Experiments
Fatty acid-free BSA (10 mg; Sigma Chemical Co., St. Louis, MO) was incubated for 1 or 4 wk at 37°C, under air, with either 100 mM glucose (Wako Pure Chemicals, Osaka, Japan), 10 mM ascorbate (Wako Pure Chemicals), 1 mM ribose (Sigma), or 10 mM arachidonate (Sigma), in 5.0 ml of 0.1 M sodium phosphate buffer (pH 7.4). Incubation was performed in the absence or presence of several concentrations of OPB-9195 (developed by Fujii Memorial Research Institute, Otsuka Pharmaceutical, Ohtsu, Japan) (9) or aminoguanidine (Tokyo Chemical Industry, Tokyo, Japan) (12). Each experiment was performed twice.

PD fluids containing 1.36% glucose (Dianeal; Baxter Healthcare, Round Lake, IL) were fortified with BSA to a final concentration of 30 mg/ml; the BSA had been dissolved in 0.1 M phosphate buffer (pH 7.4). The fluids were sterilized with a 0.22-µm-pore filter and incubated for 1 wk at 37°C, under air, in the presence or absence of several concentrations of OPB-9195 or aminoguanidine, in sealed, sterile, 1.5-ml, plastic tubes. PD fluids containing 1.36% glucose were also incubated for 24 h at 37°C, under air, in the presence of 1.0 mM OPB-9195, in sealed, sterile, 1.5-ml, plastic tubes. GO, MGO, and 3-DG contents were then determined by HPLC.

Measurement of CML, Pentosidine, MDA-Lysine, and HNE-Protein Adducts
For quantitation of CML (13), samples (100 µl) were diluted with 100 µl of 0.2 M sodium borate (pH 9.1), followed by the addition of 20 µl of 1 M NaBH4 in 0.1 N NaOH. Reduction was performed for 4 h at room temperature, and then protein was precipitated by the addition of an equal volume of 20% TCA. Protein was pelleted by centrifugation at 2000 x g for 5 min. The supernatant was discarded, and the pellet was washed with 500 µl of 10% TCA. Heavy labeled internal standards ([2H4]CML) were added, and the samples were hydrolyzed in 0.3 ml of 6 N HCl at 110°C for 16 h. The hydrolysates were dried under a stream of nitrogen. CML in the hydrolysates was measured as its N,O-trifluoroacetyl methyl esters by gas chromatography/mass spectrometry with selected-ion monitoring, as described previously (14). The CML and [2H4]CML standards (15) were gifts from Dr. John W. Baynes (University of South Carolina, Columbia). The limit of detection was 1.0 pmol CML/mg albumin.

For quantitation of pentosidine (16), each sample (50 µl) was mixed with an equal volume of 10% TCA and centrifuged at 5000 x g for 5 min. The supernatant was discarded and the pellet was washed with 300 µl of 5% TCA. The pellet was then dried under a vacuum, hydrolyzed with 100 µl of 6 N HCl for 16 h at 110°C under nitrogen, neutralized with 100 µl of 5 N NaOH and 200 µl of 0.5 M phosphate buffer (pH 7.4), filtered through a 0.5-µm-pore filter, and finally diluted with phosphate-buffered saline. Pentosidine levels in these specimens were analyzed by reverse-phase HPLC, using our previous method (17). Briefly, a 50-µl aliquot of the acid hydrolysate was injected into an HPLC system and separated on a C18 reverse-phase column (Waters, Tokyo, Japan). The effluent was monitored using a fluorescence detector (RF-10A; Shimadzu, Kyoto, Japan), with excitation and emission wavelengths of 335 and 385 nm, respectively. Synthetic pentosidine (17) was used to obtain a standard curve. The limit of detection was 0.1 pmol pentosidine/mg albumin.

MDA-lysine was measured using a colorimetric assay kit (BIOXYTECKH LPO-586; OXIS International, Portland, OR). HNE-protein adduct (18) was determined by using a previously described enzyme-linked immunosorbent assay method (19). The determinations of each AGE or ALE were performed in duplicate, and values were averaged. To reduce interassay variability, all determinations for one incubation experiment were performed simultaneously in one batch. Nevertheless, despite strictly controlled conditions, significant interassay variations were observed for experiments performed several months apart.

HPLC Analysis of GO, MGO, and 3-DG
HPLC was used to identify and quantitate three major glucose degradation products in commercial glucose-based PD fluids for which pure standards are available (GO, MGO, and 3-DG) (20,21). The standards were used for calibration purposes. One hundred microliters of sample were mixed with 100 µl of 50 µM 2,3-butanedione (internal standard), 80 µl of 2 M perchloric acid, and 40 µl of 1% o-phenylenediamine. After incubation of the mixture at 25°C for 1 h, quinoxaline derivatives were analyzed by reverse-phase HPLC, using a Waters Purecil C18 column (5 µm, 4.6 x 250 mm) and absorbance detection at 315 nm. The buffer gradient used for elution was 15 to 30% buffer B (85 to 70% buffer A) in 25 min; buffer A was 0.10% trifluoroacetic acid and buffer B was 80% acetonitrile containing 0.08% trifluoroacetic acid.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Inhibition of AGE Formation from Various Precursors
Incubation of BSA for 4 wk with either glucose or ascorbate yielded a time-dependent increase in two AGE (CML [Figure 1A] and pentosidine [Figure 1B]) residues on BSA. Incubation of BSA for 1 wk with ribose yielded a similar increase in the pentosidine level (259 pmol/mg). Incubation of BSA for 4 wk with arachidonate yielded a time-dependent increase in CML but not pentosidine levels. Pentosidine is thus derived almost exclusively from carbohydrates, whereas CML is derived from both carbohydrates and lipids.



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  		Figure 1. Formation of advanced glycation end products (AGE) and advanced lipoxidation end products (ALE) on bovine serum albumin (BSA) with various precursors. BSA (2 mg/ml) was incubated for 4 wk at 37°C with either 100 mM glucose, 10 mM arachidonate, or 10 mM ascorbate, in 0.1 M phosphate buffer (pH 7.4). Each experiment was performed twice. The yields of N{epsilon}-carboxymethyllysine (CML) (A), pentosidine (B), malondialdehyde (MDA)-lysine (C), and 4-hydroxynonenal (HNE)-protein adducts (D) in the incubation mixtures were determined in duplicate at intervals, and the results were averaged. Each individual point represents one experiment ({circ}, glucose; {triangleup}, arachidonate; {square}, ascorbate; [UNK], control BSA). When the two values were indistinguishable from each other, only one point is indicated. As a result of interassay variability, values obtained at 1 or 4 wk may not be comparable to those of Figures 2 and 3, despite identical substrate concentrations.

 



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  		Figure 2. Inhibition of AGE formation with various precursors. BSA (2 mg/ml) was incubated at 37°C for 1 wk with 1 mM ribose (A) or for 4 wk with either 100 mM glucose (B and D), 10 mM arachidonate (F), or 10 mM ascorbate (C and E), in 0.1 M phosphate buffer (pH 7.4), in the presence of several concentrations of OPB-9195 ([UNK]) or aminoguanidine ({circ}). Each experiment was performed twice. The yields of pentosidine (A to C) and CML (D to F) at the end of each incubation were determined in duplicate, and the results were averaged. Each point represents one experiment. As a result of interassay variability, values obtained at 4 wk may not be comparable to those of Figure 1, despite identical substrate concentrations.

 


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  		Figure 3. Inhibition of lipid-derived ALE formation. BSA (2 mg/ml) was incubated for 4 wk at 37°C with 10 mM arachidonate in 0.1 M phosphate buffer (pH 7.4), in the presence of several concentrations of OPB-9195 ([UNK]) or aminoguanidine ({circ}). Each experiment was performed twice. The yields of MDA-lysine (A) and HNE-protein adduct (B) at the end of each incubation were determined in duplicate, and the results were averaged. Each point represents one experiment. As a result of interassay variability, values obtained at 4 wk may not be comparable to those of Figure 1, despite identical substrate concentrations.

 
OPB-9195 and aminoguanidine inhibited, in a dose-dependent manner, the formation of pentosidine and CML on BSA after a 1-wk incubation with ribose, glucose, ascorbate, or arachidonate (Figure 2). Concentrations producing half-maximal inhibition (IC50) were calculated using regression analysis. OPB-9195 IC50 values were 0.072, 1.66, and 1.12 mM for ribose-, glucose-, and ascorbate-derived pentosidine, respectively (Figure 2, A to C). OPB-9195 IC50 values were 1.27, 2.29, and 0.77 mM for glucose-, ascorbate-, and arachidonate-derived CML, respectively (Figure 2, D to F). On a molar basis, inhibition of pentosidine and CML formation with OPB-9195 was strikingly more efficient than with aminoguanidine. At 0.625 mM, OPB-9195 and aminoguanidine inhibited 90.5 and 13.1%, respectively, of the ribose-derived pentosidine formation. At 10 mM, OPB-9195 and aminoguanidine inhibited 92.8 and 47.4% of the glucose-derived pentosidine formation and 99.4 and 46.8% of the ascorbate-derived pentosidine formation, respectively. At 10 mM, OPB-9195 inhibited 92.7, 85.3, and 74.1% of the glucose-, ascorbate-, and arachidonate-derived CML formation, respectively, whereas a similar aminoguanidine concentration inhibited only 46.2, 49.7, and 46.3% of the glucose-, ascorbate-, and arachidonate-derived CML formation, respectively.

Inhibition of Lipid-Derived ALE Formation
ALE (MDA-lysine [Figure 1C] and HNE-protein adduct [Figure 1D]), remained undetectable on BSA incubated for 4 wk with either glucose or ascorbate. In contrast, a 4-wk incubation of BSA with arachidonate yielded time-dependent increases in the levels of both MDA-lysine and HNE-protein adduct. These two ALE thus seem to be derived almost exclusively from lipids.

OPB-9195 and aminoguanidine inhibited, in a dose-dependent manner, the formation of both ALE (MDA-lysine and HNE-protein adduct). After a 4-wk incubation with arachidonate, OPB-9195 IC50 values were 1.28 and 0.81 mM for arachidonate-derived MDA-lysine (Figure 3A) and HNE-protein adduct (Figure 3B), respectively. Corresponding values for aminoguanidine were 1.82 and 1.00 nM, respectively, demonstrating an efficacy similar to that of OPB-9195.

Inhibition of AGE Formation in PD Fluid
As shown in Figure 4, a 1-wk incubation of BSA with PD fluid yielded a time-dependent increase in pentosidine and CML levels (0.88 and 133 pmol/mg for pentosidine and CML, respectively), whereas MDA-lysine and HNE-protein adduct remained undetectable (data not shown). The addition of OPB-9195 or aminoguanidine to PD fluids reduced the generation of pentosidine and CML. Here also OPB-9195 compared favorably with aminoguanidine. Pentosidine and CML levels were reduced to 0.31 and 49.7 pmol/mg by 1.0 mM OPB-9195 and to 0.48 and 55.3 pmol/mg by 1.0 mM aminoguanidine, respectively. Fifty percent inhibition was achieved at OPB-9195 concentrations of 0.26 and 0.35 mM for pentosidine and CML and at aminoguanidine concentrations of 1.50 and 0.55 mM for pentosidine and CML, respectively.



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  		Figure 4. Inhibition of AGE formation in peritoneal dialysis (PD) fluids. BSA (30 mg/ml) was incubated for 1 wk with commercial heat-sterilized PD fluids (1.36% glucose) in 0.1 M phosphate buffer (pH 7.4), in the presence of several concentrations of OPB-9195 ([UNK]) or aminoguanidine ({circ}). Each experiment was performed twice. The contents of pentosidine (A) and CML (B) were determined in duplicate at the end of the incubation, and the results were averaged. Each point represents one experiment.

 

Several RCO, such as GO, MGO, and 3-DG, are present in heat-sterilized glucose-based PD fluid. As shown in Figure 5, their concentrations were dramatically decreased within 24 h of incubation of PD fluids with OPB-9195 or aminoguanidine.



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  		Figure 5. Effects of OPB-9195 or aminoguanidine on reactive carbonyl compounds (RCO) contained in commercial heat-sterilized PD fluid. PD fluids (1.36% glucose) were incubated for 24 h in the presence of 1.0 mM OPB-9195 ([UNK]) or aminoguanidine ({circ}) or their absence ({triangleup}). The glyoxal (A), methylglyoxal (B), and 3-deoxyglucosone (C) contents in PD fluid were determined in duplicate by HPLC, before and after incubation. Data from two experiments are shown.

 


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Elevated levels of AGE and ALE are thought to contribute to uremic toxicity. This study further delineates the mechanisms by which their production might be reduced by an exogenous drug (OPB-9195). More pentosidine is generated in uremic plasma than in normal plasma incubated for 1 to 4 wk, and the process is inhibited by OPB-9195 as well as by aminoguanidine (1). Pentosidine, which was used here as a surrogate marker of AGE, is formed by the Maillard reaction from RCO produced (at least in some cases) by the oxidation of various substrates. The enhanced production of pentosidine in uremic plasma could result from various factors, e.g., elevated circulating levels of catalysts of the Maillard reaction or increased plasma concentrations of RCO, secondary either to increased production attributable to oxidative stress or to the retention of RCO by the failing kidney (4).

These in vitro observations provide a better defined framework to understand the effects of OPB-9195. First, we demonstrated that the effects of OPB-9195 extend not only to pentosidine but also to CML, thus validating the use of pentosidine as a surrogate marker of AGE formation. Second, we separately evaluated three substrates (ribose, glucose, and ascorbate), all of which are known to yield AGE. Interestingly, OPB-9195 was equally effective in preventing pentosidine and CML formation from the different substrates. The effects of OPB-9195 do not require the presence of uremic toxins or possible catalysts of the Maillard reaction, because effects were demonstrable in the absence of uremic plasma. OPB-9195 and aminoguanidine might act by an antioxidative mechanism, inhibiting the production of active RCO from the various substrates. Alternatively, these compounds might trap the available RCO and thus prevent AGE formation. The latter hypothesis is strongly supported by the observation that both OPB-9195 and aminoguanidine markedly decrease, within 24 h in vitro and in the absence of BSA, the levels of RCO (such as MGO, GO, and 3-DG) present in heat-sterilized PD fluids.

We also demonstrated that OPB-9195 inhibits not only AGE but also ALE formation in the presence of arachidonate. Similarly to its effect on AGE formation, OPB-9195 may trap the RCO produced from arachidonate and thus prevent the formation of MDA-lysine and HNE-protein adduct, which were used here as surrogate markers of ALE genesis.

Figure 6 presents the proposed reaction pathway for the trapping of RCO by OPB-9195 and aminoguanidine. The hydrazine nitrogen atom of OPB-9195 is able to react with carbonyl groups, directly or via the free base after hydrolysis, eventually forming hydrazone. This mechanism is similar to that proposed for aminoguanidine (22). However, OPB-9195 is expected to be more effective than aminoguanidine, because the hydrazine nitrogen atom of the latter has decreased nucleo-philicity as a result of the proximity of the guanidinium cation. Indeed, OPB-9195 is more effective than aminoguanidine in inhibiting in vitro pentosidine formation in uremic plasma (1), protein carbonyl formation (23), and in vitro pentosidine formation from various substrates (this study).



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  		Figure 6. Proposed reaction pathway for trapping of RCO by OPB-9195 (A) and aminoguanidine (B). OPB-9195 (I) reacts with RCO (II), directly and/or via the free base (III) after hydrolysis, to yield hydrazones (IV), by mechanisms similar to that of aminoguanidine (V).

 

The glucose-derived RCO present in PD fluids have been implicated in the advanced glycation of peritoneal membrane proteins (6,24,25,26). In an effort to reduce the levels of these compounds, glucose has been replaced by other osmotic agents, such as icodextrin (27) and amino acids (28). Until now, however, these new PD fluids could not completely replace traditional glucose-containing solutions. Compounds known to inhibit AGE formation might provide an alternative strategy. The data presented here demonstrated that 1.0 mM OPB-9195 significantly reduced the generation of pentosidine and CML, by 64 and 62%, respectively, in heat-sterilized PD fluid incubated for 1 wk. These results are in agreement with those of Lamb et al. (29), who reported that 25 mM aminoguanidine inhibited by 50% the fluorescence intensity of albumin incubated for 10 days in heat-sterilized PD fluid. Although the molecular counterparts of the fluorescence monitored in this assay have been assumed to be AGE, their identity remains unknown.

The fact that OPB-9195 also inhibits the formation of ALE is of special interest for patients undergoing PD. During PD, lipid-derived precursors of ALE may diffuse from the blood into the peritoneum and may contribute to ALE formation; indeed, ALE can be identified, by immunohistochemical analysis, in the peritoneal tissues of patients undergoing long-term PD (30).

It remains to be determined whether the in vitro effect of OPB-9195 is matched in vivo by decreased AGE and ALE deposition in joint, vascular, and peritoneal membrane proteins of uremic subjects. If this effect can be demonstrated, OPB-9195 might prove to be clinically useful to prevent not only uremic toxicity but also other diseases in which AGE and ALE are implicated, such as diabetes and atherosclerosis, as well as chronic age-dependent chemical modifications of tissue proteins.


   Acknowledgments
 
This study was supported by grants from the Research for the Future Program of the Japan Society for the Promotion of Science (Grant 96L00303) and the Japanese Ministry of Health and Welfare for Research on Health Services (Grant H10-079).


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication September 9, 1999. Accepted for publication December 29, 1999.




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