Evidence for the involvement of N-methylthiourea, a ring cleavage metabolite, in the hepatotoxicity of methimazole in glutathione-depleted mice: structure-toxicity and metabolic studies

Chem Res Toxicol. 2000 Mar;13(3):170-6. doi: 10.1021/tx990155o.


In mice depleted of GSH by treatment with buthionine sulfoximine (BSO), methimazole (2-mercapto-1-methylimidazole, MMI) causes liver injury characterized by centrilobular necrosis of hepatocytes and an increase in serum alanine transaminase (SALT) activity. MMI requires metabolic activation by both P450 monooxygenase and flavin-containing monooxygenase (FMO) before it produces the hepatotoxicity. MMI and its analogues were examined for the ability to increase SALT activity in GSH-depleted mice. Saturation of the C-4,5 double bond in MMI resulted in a complete loss of hepatotoxicity. Similarly, ring fusion of a benzene nucleus to the C-4,5 double bond, forming 2-mercapto-1-methylbenzimidazole, abolished the toxic potency. As for MMI, 2-mercapto-1,4,5-trimethylimidazole, and 2-mercapto-1-methyl-4, 5-di-n-propylimidazole, the toxic potency decreased with the increasing bulk of the 4- and 5-alkyl substituents. Furthermore, methylation of the thiol group of MMI totally reduced its toxicity. These structural requirements and the known toxicity of thiono-sulfur compounds led us to the hypothesis that MMI would undergo epoxidation of the C-4,5 double bond by P450 enzymes and, after being hydrolyzed, the resulting epoxide would be then decomposed to form N-methylthiourea, a proximate toxicant. Before N-methylthiourea would produce toxicity, it would be further biotransformed to its S-oxidized metabolites mainly by FMO. Evidence for this hypothesis was provided by the facts that N-methylthiourea and glyoxal as the accompanying fragment were identified as urinary metabolites in mice treated with MMI and that N-methylthiourea caused a marked increase in SALT activity when administered to mice in combination with BSO.

MeSH terms

  • Animals
  • Buthionine Sulfoximine / toxicity
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / metabolism
  • Disease Models, Animal
  • Gas Chromatography-Mass Spectrometry
  • Glutathione / deficiency*
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Methimazole / chemistry
  • Methimazole / metabolism
  • Methimazole / toxicity*
  • Mice
  • Mice, Inbred ICR
  • Necrosis
  • Structure-Activity Relationship
  • Thiourea / analogs & derivatives*
  • Thiourea / toxicity


  • Buthionine Sulfoximine
  • Methimazole
  • N-methylthiourea
  • Glutathione
  • Thiourea