Nephrotoxic and hepatotoxic potential of imidazolidinedione-, oxazolidinedione- and thiazolidinedione-containing analogues of N-(3,5-dichlorophenyl)succinimide (NDPS) in Fischer 344 rats

Kennedy, Erica L.; Tchao, Ruy; Harvison, Peter J.

doi:10.1016/s0300-483x(02)00692-3

Cited by 18 publications

(31 citation statements)

References 33 publications

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“…DCPT-induced hepatotoxicity was characterized by centrilobular necrosis, hepatocyte swelling, nuclear condensation and elevated serum alanine aminotransferase (ALT) levels. In contrast, DCPT had only mild toxic effects on rat kidney function and morphology (Kennedy et al, 2003;Patel et al, 2008).…”

Section: Introductionmentioning

confidence: 96%

“…E-mail: p.harvis@usp.edu;215-596-8979 (phone);215-895-1161 (fax).1971). As part of a structure-activity relationship study into the mechanism of toxicity for these types of compounds, we discovered that DCPT produced hepatotoxicity in male Fischer 344 rats (Kennedy et al, 2003). The liver damage associated with DCPT was subsequently found to be dose-, time-and gender-dependent (Patel et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…This is due, at least in part, to the fact that the glitazones are not hepatotoxic in any common laboratory animal species (Smith, 2003;Chojkier, 2005;Ong et al, 2007). Since it produces liver damage in rats (Kennedy et al, 2003;Patel et al, 2008) DCPT may be a useful model compound to explore the potential role of a TZD ring in chemically-induced hepatotoxicity. However, it should be noted that the substitution pattern in the TZD ring of DCPT differs from that in the glitazones (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Although liver damage in rats has been reported with the DCBs (Stine et al, 1991;Valentovic et al, 1993), we believe that the TZD ring is the crucial structural feature for DCPT-induced hepatotoxicity. This premise is based partly on the fact that close structural analogues of DCPT, which contain either a 2,5-pyrrolidinedione (succinimide) or 2,4-oxazolidinedione ring instead of a TZD ring, did not produce any liver damage in rats (Kennedy et al, 2003). Even among the DCBs, toxicity is dependent on the chlorine substitution pattern, with 1,2-DCB producing the largest elevations in serum ALT levels at comparable doses of the three isomers (Stine et al, 1991;Valentovic et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we found that DCPT was less hepatotoxic in female versus male rats, which could be due to a gender-based difference in metabolism (Patel et al, 2008). The centrilobular nature of DCPT-induced liver damage (Kennedy et al, 2003;Patel et al, 2008) suggests that hepatic CYPs may be involved in DCPT metabolic activation (Lindros, 1997). To achieve our goals we used two approaches: (1) rats were pretreated with CYP inhibitors prior to hepatotoxic doses of DCPT; and (2) rats were pretreated with a CYP inducer prior to a non-hepatotoxic dose of DCPT.…”

Section: Introductionmentioning

confidence: 99%

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Role of biotransformation in 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione-induced hepatotoxicity in Fischer 344 rats

et al. 2008

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Cytochrome P450 (CYP)-mediated metabolism in the thiazolidinedione (TZD) ring may contribute to the hepatotoxicity of the insulin-sensitizing agents such as troglitazone. We were interested in determining if biotransformation could also be a factor in the liver damage associated with another TZD ring containing compound, 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT). Therefore, hepatotoxic doses of DCPT (0.6 or 1.0 mmol/kg, i.p.) were administered to male Fischer 344 rats after pretreatment with vehicle, 1-aminobenzotriazole (ABT, non-selective CYP inhibitor) and troleandomycin (TAO, CYP3A inhibitor). Alternatively, rats were pretreated with vehicle or the CYP3A inducer dexamethasone (DEX) prior to a non-toxic DCPT dose (0.2 mmol/kg, i.p.). Vehicle-, ABT-, TAO-and DEX-only control groups were also run. Toxicity was assessed 24 hours after DCPT administration. Both hepatotoxic doses of DCPT induced elevations in serum alanine aminotransferase (ALT) levels that were attenuated by ABT or TAO pretreatment. Liver sections from rats that received vehicle + DCPT revealed areas of gross necrosis and neutrophil invasion, whereas sections from ABT + DCPT and TAO + DCPT rats showed minor changes compared to controls. DEX pretreatment potentiated ALT levels associated with the non-toxic DCPT dose. Furthermore, DEX + DCPT rat liver sections exhibited hepatic injury when compared against rats that received vehicle + DCPT. Blood urea nitrogen levels, urinalysis and kidney morphology were not markedly altered by any combination of pretreatments or treatments. Enzyme activity and Western blotting experiments with rat liver microsomes confirmed the effects of the various pretreatments. Our results suggest that hepatic CYP3A isozymes may be involved in DCPT-induced liver damage in male rats. We believe this is the first report demonstrating that modulation of the biotransformation of a TZD ring-containing compound can alter hepatotoxicity in a common animal model.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of biotransformation in 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione-induced hepatotoxicity in Fischer 344 rats

et al. 2008

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Metabolic Activation of Organic Functional Groups Utilized in Medicinal Chemistry

Kalgutkar

2011

Mass Spectrometry in Drug Metabolism and Disposition

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Effect of structural modifications on 3‐(3,5‐dichlorophenyl)‐2,4‐thiazolidinedione‐induced hepatotoxicity in Fischer 344 rats

Patel

Crincoli

Frederick

et al. 2011

J of Applied Toxicology

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Glitazones, used for type II diabetes, have been associated with liver damage in humans. A structural feature known as a 2,4-thiazolidinedione (TZD) ring may contribute to this toxicity. TZD rings are of interest since continued human exposure via the glitazones and various prototype drugs is possible. Previously, we found that 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT) was hepatotoxic in rats. To evaluate the importance of structure on DCPT toxicity, we therefore studied two series of analogues. The TZD ring was replaced with: a mercaptoacetic acid group ([[[(3,5-dichlorophenyl)amino]carbonyl]thio]acetic acid, DCTA); a methylated TZD ring (3-(3,5-dichlorophenyl)-5-methyl-2,4-thiazolidinedione, DPMT); and isomeric thiazolidinone rings (3-(3,5-dichlorophenyl)-2- and 3-(3,5-dichlorophenyl)-4-thiazolidinone, 2-DCTD and 4-DCTD, respectively). The following phenyl ring-modified analogues were also tested: 3-phenyl-, 3-(4-chlorophenyl)-, 3-(3,5-dimethylphenyl)- and 3-[3,5-bis(trifluoromethyl)phenyl]-2,4-thiazolidinedione (PTZD, CPTD, DMPT and DFMPT, respectively). Toxicity was assessed in male Fischer 344 rats 24 hours after administration of the compounds. In the TZD series only DPMT produced liver damage, as evidenced by elevated serum alanine aminotransferase (ALT) activities at 0.6 and 1.0 mmol/kg (298.6 ± 176.1 and 327.3 ± 102.9 Sigma-Frankel units/ml, respectively) versus corn oil controls (36.0 ± 11.3) and morphological changes in liver sections. Among the phenyl analogues, hepatotoxicity was observed in rats administered PTZD, CPTD and DMPT; with ALT values of 1196.2 ± 133.6, 1622.5 ± 218.5 and 2071.9 ± 217.8, respectively (1.0 mmol/kg doses). Morphological examination revealed severe hepatic necrosis in these animals. Our results suggest that hepatotoxicity of these compounds is critically dependent on the presence of a TZD ring and also the phenyl substituents.

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Nephrotoxic and hepatotoxic potential of imidazolidinedione-, oxazolidinedione- and thiazolidinedione-containing analogues of N-(3,5-dichlorophenyl)succinimide (NDPS) in Fischer 344 rats

Cited by 18 publications

References 33 publications

Role of biotransformation in 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione-induced hepatotoxicity in Fischer 344 rats

Role of biotransformation in 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione-induced hepatotoxicity in Fischer 344 rats

Metabolic Activation of Organic Functional Groups Utilized in Medicinal Chemistry

Effect of structural modifications on 3‐(3,5‐dichlorophenyl)‐2,4‐thiazolidinedione‐induced hepatotoxicity in Fischer 344 rats

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