N-oxygenation of stobadine, a gamma-carboline antiarrhythmic and cardioprotective agent: the role of flavin-containing monooxygenase.

1. N-oxygenation of stobadine, a gamma-carboline antiarrhythmic and cardioprotective agent, was investigated in vitro using rat liver preparations. 2. Stobadine N-oxygenase activity was located mainly in the microsomal fraction and exhibited a requirement for oxygen and NADPH. The apparent Km and Vmax values for the process were, respectively, 350 microM and 3.48 nmol/mg protein per min. 3. N-oxygenation of stobadine in rat liver microsomes was not affected by SKF 525-A, carbon monoxide, metyrapone, cyanide or n-octylamine. When guinea-pig liver microsomes were used the reaction was activated by n-octylamine. 4. N-oxygenase activity was strongly inhibited by methimazole and depressed by phenobarbital and 3-methylcholantrene pretreatment. 5. The above results, along with the pH optimum of 8.4, strongly indicate the involvement of flavin-containing monooxygenase in the metabolic N-oxygenation of stobadine. 6. Species difference in liver microsomal N-oxygenase activity was evident, the order of activity being guinea-pig greater than rat greater than rabbit.