Methapyrilene hepatotoxicity is associated with increased hepatic glutathione, the formation of glucuronide conjugates, and enterohepatic recirculation

Ratra, Gurpreet S.; Powell, C.J.; Park, B.Kevin; Maggs, James L.; Cottrell, S.

doi:10.1016/s0009-2797(00)00253-2

Cited by 23 publications

(35 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This depletion might be a precondition for the cytotoxicity of MP, but the progression of hepatotoxicity in vivo, despite an increase in hepatic GSH, suggests otherwise. The increase in hepatic GSH, also reported previously (Ratra et al, 2000), is attributable to induction by MP of a cell defense pathway that produces significant up-regulation of glutamate-cysteine ligase catalytic subunit (C. M. Hirst, A. E. Mercer, E. E. The only previously published indication for cytotoxic MP metabolites is an attenuation of toxicity in male rat hepatocytes by the nonspecific P450 inhibitor metyrapone (Ratra et al, 1998b). This concentration-dependent cytoprotection correlated with metyrapone's inhibition of CYP2C11, but not CYP3A2, in liver microsomes of male rats.…”

Section: Discussionsupporting

confidence: 87%

“…The representative positions of GSH substitution on the thiophene rings of I and III are those reported for similar metabolites of 2-phenylthiophene . MP produces an acute hepatotoxicity in male rats at relatively low doses (Graichen et al, 1985;Ratra et al, 1998aRatra et al, , 2000Huang et al, 2004;Craig et al, 2006). The comparative mildness of this injury more typically resembles druginduced clinical hepatotoxicities than the severe damage produced in experimental animals by many other reference hepatotoxicants.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

“…The major metabolites ( Fig. 1) commonly described for the rat are desmethyl MP, MP N-oxide, (5-hydroxypyridyl)-MP O-glucuronide, and products arising from oxidative NЈ-dealkylation of the thienylmethyl moiety (Singer et al, 1987;Ratra et al, 2000). Male-specific CYP2C11 has been tentatively implicated in the biotransformation and hepatocytotoxicity of MP, but the reaction catalyzed by this isoform remains uncharacterized (Ratra et al, 1998a,b).…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

Graham¹,

Walsh²,

Hirst³

et al. 2008

J Pharmacol Exp Ther

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Graham¹,

Walsh²,

Hirst³

et al. 2008

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…However, these authors excluded the involvement of glutathione depletion followed by oxidative stress in the later paper (Ratra et al, 2000). We measured hepatic glutathione contents in rats treated with MP in a separate study (Uehara et al, submitted).…”

Section: 08e-4 9 Starch and Sucrose Metabolism (Rattus Norvegicus)mentioning

confidence: 99%

Gene expression profiling of methapyrilene-induced hepatotoxicity in rat

et al. 2008

View full text Add to dashboard Cite

-The present study was conducted as a model case of the toxicogenomics approach for analyzing toxicological mechanisms and toxicity assessments in the early stage of drug development by comparing with classical toxicology data. Methapyrilene (MP) 100 mg/kg produced obvious histopathological changes in liver of rats by single or repeated dose up to 28 days with significant elevation of ALT and AST. In the middle dose groups (30 mg/kg MP), no apparent changes were noted in blood biochemical data by single dosing or repeated dosing up to one week, and no obvious histopathological changes were observed except a slight hypertrophy in the hepatocytes. Comprehensive gene expression changes were analyzed using Affymetrix GeneChip ® and differentially expressed probe sets were statistically extracted. These contained many genes related to "glutathione metabolism", "apoptosis", "MAPK signaling pathway" and "regulation of cell cycle", which were all thought to be involved in the development of presently observed phenotypes. In the high dose groups, TGP1 scores (developed in our system in order to overview the responsiveness of drugs to multiple marker gene lists) for these categories were markedly increased from the early time point after single dose and kept their high expression throughout the repeated dose period. In the middle dose groups, the increment of the scores were noted not only at the time points when apparent pathological changes emerged, but also at the earlier stage of repeated dosing and even after single dosing. We conclude that toxicogenomics would enable a more sensitive assessment at the earlier time point than classical toxicology evaluation.

show abstract

System‐wide analysis of hepatotoxicological responses: Tissomics is key

Kriete

Boyce²,

Love³

2006

Cytometry Pt A

View full text Add to dashboard Cite

Background: Combining diverse data streams across different levels of biological observation, such as molecular, cellular, and clinical chemistry responses, support a system-wide diagnostic approach. Recent progress in slidebased cytometry contributes to the development of tissomics, a high-throughput and high-content phenotyping methodology that provides data-rich profiles of cellular heterogeneity in tissues enabling correlative statistical treatments over multiple scales of biological hierarchies. Methods: Phenotypical data are covariants that can be used as biomarkers to identify relevant candidate genes by associating initiating molecular events with phenotypical changes and adverse outcomes. We introduce a procedure of combined statistical and analytical tools to identify and visualize such associations for nonpooled entities. The new utility is applied to a time-controlled, low-dose toxi-

show abstract

Methapyrilene hepatotoxicity is associated with increased hepatic glutathione, the formation of glucuronide conjugates, and enterohepatic recirculation

Cited by 23 publications

References 34 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

Gene expression profiling of methapyrilene-induced hepatotoxicity in rat

System‐wide analysis of hepatotoxicological responses: Tissomics is key

Contact Info

Product

Resources

About