Hydrogen peroxide-dependent liver microsomal N-demethylation and N-oxygenation of stobadine, a gamma-carboline antiarrhythmic and cardioprotective agent.

1. Hydrogen peroxide was capable of supporting the N-methylation and N-oxygenation of stobadine in rat liver microsomes. NADPH and O2 were not required. 2. The metabolic conversions promoted by H2O2 were completely abolished by preheating the microsomes for 5 min at 90 degrees C prior to assay, indicating the enzymic nature of the reaction. 3. The response to phenobarbital pretreatment and to inhibitors such as SKF 525-A, metyrapone and CO indicated participation of cytochrome P-450 in its oxidized form. 4. Microsomal cytochrome P-450 could not be replaced by haemoglobin, catalase, horseradish peroxidase or by its conversion to cytochrome P-420. 5. Comparative experiments on rabbits, guinea pigs and rats showed species differences in the extent of the peroxidatic metabolism of stobadine, the order of activity not being the same for C- and N-oxidation.