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Role of CYP2A6 in Methimazole Bioactivation and Hepatotoxicity

Jianhua Li1, Zahir Hussain1, Junjie Zhu1

  • 1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.

Chemical Research in Toxicology
|November 17, 2021
PubMed

Insights

The antithyroid drug methimazole (MMI) can harm the liver. Researchers found that the enzyme CYP2A6 metabolizes MMI into a toxic compound, causing liver damage.

Area of Science:

  • Pharmacology
  • Hepatology
  • Drug Metabolism

Background:

  • Methimazole (MMI) is a common antithyroid medication.
  • MMI can cause drug-induced liver injury through mechanisms that are not fully understood.
  • Previous research suggests that hepatic metabolism of MMI produces a toxic metabolite, N-methylthiourea, implicated in liver damage.

Purpose of the Study:

  • To identify the specific enzyme responsible for metabolizing MMI into the toxic N-methylthiourea.
  • To investigate the role of cytochrome P450 enzymes (CYPs) in MMI-induced hepatotoxicity.

Main Methods:

  • Screening of various cytochrome P450 (CYP) enzymes for their ability to metabolize MMI.
  • Utilizing CYP2A6 inhibitors in mouse models to assess the impact on N-methylthiourea formation and MMI-induced hepatotoxicity.

Main Results:

  • Cytochrome P450 2A6 (CYP2A6) was identified as the primary enzyme catalyzing the conversion of MMI to N-methylthiourea.
  • Inhibition of CYP2A6 significantly reduced the formation of N-methylthiourea from MMI in mice.
  • Pretreatment with a CYP2A6 inhibitor effectively prevented MMI-induced liver injury in the animal model.

Conclusions:

  • CYP2A6 plays a critical role in the bioactivation of methimazole.
  • CYP2A6-mediated metabolism is essential for MMI-induced hepatotoxicity.
  • Targeting CYP2A6 may offer a strategy to mitigate methimazole-induced liver damage.

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