Effect of modulators of glutathione synthesis on the hepatotoxicity of 2-methylfuran.
Treatment of male Sprague-Dawley rats with buthionine sulfoximine (BSO), prior to administration of carbon-14(14C)-labelled 2-methylfuran (2MF) caused a marked decrease in the covalent binding of 14C-labelled 2MF metabolites to both DNA and protein, although there was no apparent change in the distribution of the labelled parent 2MF. BSO pretreatment also protected against hepatotoxicity of 2MF, as indicated by lower serum glutamic pyruvic transaminase (GPT) levels. Pretreatment with BSO offered protection only if administered 1.5 hr before 2MF dosage. Administration of 2MF, 4 and 6 hr after BSO resulted in manifestation of the hepatotoxicity of 2MF. Prior treatment with diethylmaleate (DEM), increased covalent binding of [14C]2MF to liver proteins and also elevated serum GPT levels. Thus, depletion of tissue glutathione (GSH) by two different chemicals acting by different mechanisms produced opposite effects on the covalent binding and toxicity of 2MF. Pretreatment with L-2-oxothiazolidine-4-carboxylate (OTZ), a promoter of GSH biosynthesis, increased the hepatic covalent binding of [14C]2MF and potentiated hepatotoxicity. However, administration of OTZ and BSO prior to an i.p. dose of 100 mg/kg of 2MF, decreased the hepatic covalent binding of [14C]2MF and decreased the hepatoxicity. The marked instability of the GSH conjugate of the reactive metabolite of 2MF may account for the potentiation of hepatotoxicity of 2MF by OTZ. A single s.c. dose of BSO, caused a transient increase in plasma cystine levels concurrent with the depletion of liver GSH. Administration of 2MF, 1.5 hr after BSO, significantly decreased plasma cystine levels as compared to control animals that received vehicle alone. Pretreatment with BSO also resulted in increased excretion of urinary metabolites in 2MF treated animals as compared to animals receiving 2MF alone. Thus, BSO probably protects against hepatoxicity of 2MF by indirectly causing more detoxification of the reactive metabolite of 2MF, as it does not alter the distribution of unmetabolized 2MF and does not have any apparent effect on the microsomal mixed-function oxidase which mediates the activation of 2MF. The enhanced detoxification of 2MF in BSO treated animals appears independent of the depleted GSH levels; it may result from increased availability of a better alternative nucleophile (i.e. cysteine), capable of conjugating with acetyl acrolein. Acetyl acrolein (AA) appears to be the principal reactive metabolite of 2MF which binds covalently to tissues. Previous in vitro studies have shown that cysteine is a better trapping agent of AA than GSH or N-acetyl-cysteine.
Ravindranath
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Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Frederick, MD 21702-1013.
Boyd
M R
MR
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000963:Antimetabolites / Q000008:administration & dosage / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D003553:Cystine / Q000097:blood; D004347:Drug Interactions; D005663:Furans / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005978:Glutathione / Q000096:biosynthesis*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines
D000963:Antimetabolites; D005663:Furans; D008298:Maleates; D013844:Thiazoles; D053778:Thiazolidines; D008717:Methionine Sulfoximine; D003553:Cystine; D019328:Buthionine Sulfoximine; C029060:2-methylfuran; D000410:Alanine Transaminase; C014476:diethyl maleate; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid