Hydrogen Peroxide-Dependent Liver Microsomal N-Demethylation and N-Oxygenation of Stobadine, a γ-Carboline Antiarrhythmic and Cardioprotective Agent

Abstract

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°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.