title: The tissue-specific toxicity of methimazole in the mouse olfactory mucosa is partly mediated through target-tissue metabolic activation by CYP2A5.
abstract: The antithyroid drug methimazole (MMZ) can cause severe, tissue-specific toxicity in mouse olfactory mucosa (OM), presumably through a sequential metabolic activation of MMZ by cytochrome P450 (P450) and flavin monooxygenases (FMO). The aims of this study were to determine whether CYP2A5, one of the most abundant P450 enzymes in the mouse OM, is involved in MMZ metabolic activation, by comparing Cyp2a5-null with wild-type (WT) mice, and whether hepatic microsomal P450 enzymes, including CYP2A5, are essential for MMZ-induced OM toxicity, by comparing liver-Cpr-null (LCN) mice, which have little P450 activity in hepatocytes, with WT mice. We showed that the loss of CYP2A5 expression did not alter systemic clearance of MMZ (at 50 mg/kg, i.p.); but it did significantly decrease the rates of MMZ metabolism in the OM, whereas FMO expression in the OM was not reduced. MMZ induced depletion of nonprotein thiols, as well as pathological changes, in the OM of WT mice; the extent of these changes was much reduced in the Cyp2a5-null mice. Thus, CYP2A5 plays an important role in mediating MMZ toxicity in the OM. In contrast, the rate of systemic clearance of MMZ was significantly reduced in the LCN mice, compared to WT mice, whereas the MMZ-induced OM toxicity was not prevented. Therefore, hepatic P450 enzymes are essential for systemic MMZ clearance, but they are not required for MMZ-induced OM toxicity. We conclude that the tissue-specific toxicity of MMZ is mediated by target tissue metabolic activation, and the reaction is partly catalyzed by CYP2A5 in the OM.
authors.affiliation: Wadsworth Center, New York State Department of Health, Albany, NY, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Genter
authors.forename: Melissa
authors.initials: M
authors.lastname: Behr
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008657:Metabolic Clearance Rate; D008713:Methimazole / Q000493:pharmacokinetics* / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009928:Organ Specificity
chemical_list: D013956:Antithyroid Agents; D008713:Methimazole; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D009251:NADPH-Ferrihemoprotein Reductase