Potentiation of thioacetamide liver injury in diabetic rats is due to induced CYP2E1

J Pharmacol Exp Ther. 2000 Aug;294(2):473-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Allyl Compounds / pharmacology
  • Animals
  • Biotransformation
  • Chemical and Drug Induced Liver Injury
  • Cytochrome P-450 CYP2E1 / biosynthesis*
  • Cytochrome P-450 CYP2E1 / metabolism
  • Cytochrome P-450 CYP2E1 Inhibitors
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / enzymology*
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Indoles / pharmacology
  • Isoniazid / pharmacology
  • Liver / drug effects
  • Liver / enzymology
  • Liver Diseases / enzymology
  • Liver Diseases / etiology*
  • Male
  • Oxygenases / antagonists & inhibitors
  • Oxygenases / metabolism
  • Rats
  • Sulfides / pharmacology
  • Thioacetamide / pharmacokinetics
  • Thioacetamide / toxicity*


  • Allyl Compounds
  • Cytochrome P-450 CYP2E1 Inhibitors
  • Enzyme Inhibitors
  • Indoles
  • Sulfides
  • Thioacetamide
  • allyl sulfide
  • indole-3-carbinol
  • Oxygenases
  • Cytochrome P-450 CYP2E1
  • dimethylaniline monooxygenase (N-oxide forming)
  • Alanine Transaminase
  • Isoniazid