Metabolism of methimazole by rat liver cytochrome P-450-containing monoxygenases.
The incubation of methimazole (1-methyl-2-thioimidazole, MMI) with rat hepatic microsomes led to the formation of 3-methyl-2-thiohydantoin and N-methylimidazole. In addition, an NADPH-stimulated binding of 14C and 35S from [14C]- and [35s]MMI to microsomal macromolecules was seen. Both the NADPH-stimulated N-methylimidazole formation and binding of radioactivity from [14C]- and [35S]MMI to microsomal macromolecules appeared to be catalyzed largely by the cytocrhome P-450 to monoxygenase systems of rat hepatic microsomes. A portion of the radioactivity bound to microsomes incubated with [14C]- and [35S]MMI was released as unchanged MMI on prolonged incubation under acid conditions; this suggests that strong binding of MMI to microsomes occurred. A portion of the 35S bound to microsomes incubated with [35S]MMI can be released as 35SCN- on incubation of the 35S-labeled microsomes with CN-. These data suggest that a portion of the sulfur released in the metabolism of MMI to N-methylimidazole is in the form of atomic sulfur (S), which binds to cysteine sulfhydryl groups (R-S-H) in microsomal proteins to form a hydrodisulfide (R-S-S-H).
D000818:Animals; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008713:Methimazole / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D013462:Sulfur Radioisotopes
D002250:Carbon Radioisotopes; D013462:Sulfur Radioisotopes; D009249:NADP; D008713:Methimazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases