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 CCl4-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.
Footnotes
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Send reprint requests to: Dr. Harihara M. Mehendale, Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, 700 University Ave., Monroe, LA 71209-0495. E-mail: pymehendale{at}alpha.ulm.edu
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↵1 This study was supported by the Louisiana Board of Regents Fund through the University of Louisiana at Monroe, Kitty DeGree Chair in Pharmacy (Toxicology). Preliminary (1999) results of this study were presented at the EB99 Annual Meeting of FASEB, Washington DC (Wang et al., 1999).
- Abbreviations:
- TA
- thioacetamide
- ALT
- alanine aminotransferase
- DAS
- diallyl sulfide
- FMO
- flavin-containing monooxygenase
- I3C
- indole-3-carbinol
- INH
- isoniazid
- PNP
- p-nitrophenol
- STZ
- streptozotocin
- Received October 15, 1999.
- Accepted March 13, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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