STUDIES ON THE O-DEMETHYLATION OF MISONIDAZOLE BY RAT-LIVER MICROSOMES

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  • 1 January 1982
    • journal article
    • research article
    • Vol. 66  (6) , 1343-1347
Abstract
The role of rat liver microsomes in the O-demethylation of [the hypoxic tumor cell radiosensitizer] misonidazole to desmethylmisonidazole was studied. The rate of the microsomal-dependent formation of desmethylmisonidazole was linear up to a protein concentration of 2 mg/ml and over a 10-min interval. The metabolism was optimal in a system comprised of microsomes, O2 and NADPH. Metabolism in incubation mixtures continuously flushed with N2 was inhibited by 78%. The O-demethylase activity was competitively inhibited by the addition of SKF 525-A [proadifen hydrochloride], with a Ki of .apprx. 1 .times. 10-5 M. The Km and Vmax values of normal microsomes were 1.87 .+-. 0.30 mM and 413 .+-. 14 pmol/min/mg of microsomal protein, respectively. Pretreatment of rats with phenobarbital for 7 days prior to preparation of the microsomes resulted in no significant change in the Km, but the Vmax was considerably increased to 1033 .+-. 203 pmol/min/mg of microsomal protein. The O-demethylation of misonidazole is apparently mediated by cytochrome P-450.