title: Potentiation of thioacetamide liver injury in diabetic rats is due to induced CYP2E1.
abstract: Thioacetamide (TA)-induced hepatotoxicity is potentiated in streptozotocin (STZ)-induced diabetic rats. The relative roles of CYP2E1 and FMO1 in the mechanism of TA-associated liver injury were investigated. In the STZ-induced diabetic rat, hepatic CYP2E1 protein concentration and p-nitrophenol hydroxylation were induced 8- and 5.6-fold, respectively. Pretreatment with the CYP2E1 inducer, isoniazid (INH, 250 mg/kg, i.p.) before TA (300 mg/kg, i.p.) administration significantly increased TA-associated liver injury as assessed by plasma alanine aminotransferase (ALT). Hepatic CYP2E1 expression and p-nitrophenol hydroxylation were induced 2.2- and 2. 5-fold in the INH-pretreated rat, respectively. Inhibition of CYP2E1 by diallyl sulfide (DAS, 200 mg/kg, p.o., two doses) before TA administration, decreased plasma ALT activity by 60% in the nondiabetic rat and by 75% in the diabetic rat. Abolition of microsomal p-nitrophenol hydroxylation and CCl(4)-induced liver injury confirmed that hepatic CYP2E1 was highly inhibited by DAS. Hepatic flavin-containing monooxygenase (FMO) form 1 expression and methimazole-dependent oxidation of thiocholine were induced 2.5- and 1.8-fold in the diabetic rat, respectively. Dietary administration of 0.25% indole-3-carbinol (I3C) for 10 days inhibited FMO1 expression and enzyme activity in both nondiabetic and diabetic rats. Paradoxically, TA-induced liver injury was increased in these I3C-pretreated rats. These findings indicate that hepatic CYP2E1 appears to be primarily involved in bioactivation of TA. In the STZ-induced diabetic rat, diabetes-induced CYP2E1 appears to be responsible for the potentiated liver injury; Even though hepatic FMO1 is induced in the diabetic rat, it is unlikely to mediate the potentiated TA hepatotoxicity.
authors.affiliation: Division of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, 71209-0495, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Shankar
authors.forename: M J
authors.initials: MJ
authors.lastname: Ronis
authors.forename: H M
authors.initials: HM
authors.lastname: Mehendale
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007538:Isoniazid / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008107:Liver Diseases / Q000201:enzymology / Q000209:etiology*; D008297:Male; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D013440:Sulfides / Q000494:pharmacology; D013853:Thioacetamide / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D000498:Allyl Compounds; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D013440:Sulfides; D013853:Thioacetamide; C038491:allyl sulfide; C016517:indole-3-carbinol; D010105:Oxygenases; D019392:Cytochrome P-450 CYP2E1; C020066:dimethylaniline monooxygenase (N-oxide forming); D000410:Alanine Transaminase; D007538:Isoniazid