Methapyrilene hepatotoxicity is associated with oxidative stress, mitochondrial disfunction and is prevented by the Ca2+ channel blocker verapamil

Ratra, Gurpreet S.; Morgan, Winston A.; Mullervy, Jenny; Powell, C.J.; Wright, Matthew C.

doi:10.1016/s0300-483x(98)00096-1

Cited by 44 publications

(55 citation statements)

References 53 publications

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“…Coincubation with a 5-fold molar excess of a thiol (1 mM GSH, GSH-EE, or NAC), in contrast to the coincubation with dithiothreitol, which is known to have a cytoprotective action (Ratra et al, 1998b), did not affect the cytotoxicity of MP (data not shown).…”

Section: Toxicity Of Mp and Side-chain Ring Analogs In Hepatocytesmentioning

confidence: 92%

“…Typical hepatotoxic regimens (150 -300 mg/kg/day ϫ 3) produce a mild to moderate injury characterized by hepatocellular necrosis, bile duct proliferation, and inflammatory cell infiltration. MP is also toxic to isolated rat hepatocytes (McQueen and Williams, 1982;Ratra et al, 1998b), which are reported to be more susceptible than mouse hepatocytes (Kelly et al, 1992).MP has come to be regarded as a model investigatory compound among drug hepatotoxicants, and it is used fre- Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.135483.…”

mentioning

confidence: 99%

“…However, although the cytotoxicity has been associated with metabolic activation, oxidative stress, mitochondrial damage (Ratra et al, 1998a;Ratra et al, 1998b), protein modification, and altered protein expression (Craig et al, 2006), its mechanism is still obscure and the toxicophore is unidentified.…”

mentioning

confidence: 99%

“…The drug-induced hepatotoxicity is considered to be metabolism-dependent because it is diminished by agents that inhibit cytochrome P450 (P450): cobalt protoporphyrin in vivo (Ratra et al, 1998a) and metyrapone in rat hepatocytes (Ratra et al, 1998b). The major metabolites ( Fig.…”

mentioning

confidence: 99%

“…Differences between the metabolism of MP in rats and mice are both qualitative and quantitative (Lampe and Kammerer, 1990), but they have not provided a rigorously tested metabolic explanation of the greater susceptibility of rat hepatocytes (Kelly et al, 1992). Although metabolites of MP have been postulated as causal to the hepatotoxicity of the drug (Singer et al, 1987;Kelly et al, 1992;Ratra et al, 1998b), this toxicity has not been linked experimentally with either metabolic activation, as represented by irreversible drug binding, or any stable metabolites of MP derived from reactive intermediates. We have re-examined the metabolism and cytotoxicity of radiolabeled MP in rodent hepatocytes to elucidate metabolic mechanisms of hepatotoxicity.…”

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confidence: 99%

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Identification of the Thiophene Ring of Methapyrilene as a Novel Bioactivation-Dependent Hepatic Toxicophore

Graham¹,

Walsh²,

Hirst³

et al. 2008

J Pharmacol Exp Ther

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Methapyrilene (MP), a 2-thiophene H 1 -receptor antagonist, is a model toxicant in the genomic and proteomic analyses of hepatotoxicity. In rats, it causes an unusual periportal necrosis that is hypothetically attributed to chemically reactive and cytotoxic metabolites. We have characterized the bioactivation of MP by hepatic microsomes and primary rat hepatocytes, and we established a possible causal linkage with cytotoxicity. Methapyrilene tritiated at C-2 of the diaminoethane moiety ([ 3 H]MP) was metabolized via an NADPH-dependent pathway to intermediates that combined irreversibly with microsomes (rat Ͼ mouse Ϸ human). This binding was attenuated by the cytochrome P450 (P450) inhibitor 1-aminobenzotriazole and thiols but not by trapping agents for iminium ions and aldehydes. Reactive intermediates were trapped as thioether adducts of monooxygenated MP. Mass spectrometric and hydrogen/deuterium exchange analysis of the glutathione adduct produced by rat liver microsomes indicated that the metabolite was most probably a thioether of MP S-oxide substituted in the thiophene ring. The glutathione adduct was formed by rat hepatocytes and eliminated in bile by rats administered [ 3 H]MP intravenously. MP produced concentration-and time-dependent cytotoxicity, depleted glutathione, and underwent irreversible binding to the hepatocytes before a significant increase in cell damage was observed. P450 inhibitors reduced turnover of the drug, production of the glutathione adduct, irreversible binding, and cytotoxicity but inhibited glutathione depletion selectively. MP underwent lesser turnover and bioactivation in mouse hepatocytes and was not cytotoxic. Analogs with phenyl and p-methoxyphenyl rings were much less hepatocytotoxic than MP. Hepatotoxicity in rats was diminished by predosing with 1-aminobenzotriazole. For the first time, a thiophene ring substituent is identified as a bioactivation-dependent toxicophore in hepatocytes. Fig. 1], a 2-thiophene H 1 -receptor antagonist, was not associated with hepatotoxicity in humans, but it causes unusual dose-dependent periportal damage in adult male rats (Graichen et al., 1985;Ratra et al., 1998a;Ratra et al., 2000). Typical hepatotoxic regimens (150 -300 mg/kg/day ϫ 3) produce a mild to moderate injury characterized by hepatocellular necrosis, bile duct proliferation, and inflammatory cell infiltration. MP is also toxic to isolated rat hepatocytes (McQueen and Williams, 1982;Ratra et al., 1998b), which are reported to be more susceptible than mouse hepatocytes (Kelly et al., 1992).MP has come to be regarded as a model investigatory compound among drug hepatotoxicants, and it is used fre- Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.135483.ABBREVIATIONS: MP, methapyrilene; P450, cytochrome P450; tGSH, total glutathione (GSH plus glutathione disulfide); MeOD, monodeuteromethanol; HPLC, high-performance liquid chromatography; [ 3 H]MP, methapyrilene tritiated at C-2 of the diaminoethane moie...

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Section: Toxicity Of Mp and Side-chain Ring Analogs In Hepatocytesmentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of the Thiophene Ring of Methapyrilene as a Novel Bioactivation-Dependent Hepatic Toxicophore

Graham¹,

Walsh²,

Hirst³

et al. 2008

J Pharmacol Exp Ther

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Protein expression analysis of drug-mediated hepatotoxicity in the Sprague-Dawley rat

Man¹,

White²,

Bryant³

et al. 2002

Proteomics

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This study has investigated the protein changes in rat liver elicited by a group of model hepatotoxicants, methapyrilene, cyproterone acetate and dexamethasone and offers a compelling argument in support of the use of two-dimensional polyacrylamide gel electrophoresis and mass spectrometry for the identification of compound specific biomarkers. The different treatments caused distinct changes to the rat liver proteome. Many of the protein changes could be associated with the known pharmacological and toxicological mechanisms of action of these drugs, whereas for other proteins, the rationale behind the alterations was less obvious. Furthermore, these changes can be used to classify the treatments with a view to utilising them as 'molecular signatures' to further our understanding of less well studied drugs such as SKF-106686 (an adrenoreceptor agonist). This approach has the potential for opening up new avenues for the exploration of molecular mechanisms of toxicity. This paper has explored the feasibility of proteomics to provide valuable information on the biochemical consequences elicited by hepatototoxic drugs.

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The Role of Drug Metabolism in Toxicity

Davis

Hanumegowda

2008

Drug Metabolism Handbook

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Methapyrilene hepatotoxicity is associated with oxidative stress, mitochondrial disfunction and is prevented by the Ca2+ channel blocker verapamil

Cited by 44 publications

References 53 publications

Identification of the Thiophene Ring of Methapyrilene as a Novel Bioactivation-Dependent Hepatic Toxicophore

Identification of the Thiophene Ring of Methapyrilene as a Novel Bioactivation-Dependent Hepatic Toxicophore

Protein expression analysis of drug-mediated hepatotoxicity in the Sprague-Dawley rat

The Role of Drug Metabolism in Toxicity

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