OLFACTORY TOXICITY OF METHIMAZOLE - DOSE-RESPONSE AND STRUCTURE-ACTIVITY STUDIES AND CHARACTERIZATION OF FLAVIN-CONTAINING MONOOXYGENASE ACTIVITY IN THE LONG-EVANS RAT OLFACTORY MUCOSA

Methimazole is a compound administered to humans for the treatment of hyperthyroidism and is used experimentally as a model substrate for th e flavin-containing monooxygenase (FMO) system. Previous results from this laboratory demonstrated that methimazole is an olfactory system t oxicant, causing nearly complete destruction of the olfactory epitheli um in the male Long-Evans rat following a single ip dose of 300 mg/kg. The present studies were undertaken to determine the dose-response re lationship for methimazole-induced olfactory mucosal damage and to det ermine whether or not similar damage occurs as a result of oral admini stration, mimicking the relevant route of human exposure. We also inve stigated the mechanism of olfactory toxicity of methimazole by means o f a structure-activity study and began the characterization of the for m(s) of FMO present in the olfactory mucosa of the male Long-Evans rat . Dose-response analysis demonstrated that methimazole causes olfactor y mucosal damage at doses of 25 mg/kg ip and greater. The results of g avage studies showed that a single oral dose of 50 mg/kg also caused o lfactory mucosal damage. Two structurally related compounds, methylimi dazole and methylpyrrole, were not olfactory toxicants, suggesting tha t a reactive intermediate generated in the course of metabolizing meth imazole to an S-oxide is the olfactory toxic species. Microsomal incub ation studies revealed the presence of methimazole S-oxidation activit y in olfactory mucosal microsomes at levels comparable to those in liv er. An anti-mouse liver FMO antibody reacted on Western blots with olf actory mucosal microsomes. These findings demonstrate a dose-response for the olfactory toxicity of methimazole and suggest that characteriz ation of human olfactory mucosal FMO activity may be necessary to asse ss the potential for human risk associated with therapeutic exposure t o methimazole.