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.
Stefek
M
M
Institute of Experimental Pharmacology, Centre of Physiological Sciences, Slovak Academy of Sciences, Bratislava, Czechoslovakia.
Benes
L
L
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D001711:Biotransformation; D002243:Carbolines / Q000378:metabolism*; D002849:Chromatography, Gas; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D000889:Anti-Arrhythmia Agents; D002243:Carbolines; D006861:Hydrogen Peroxide; C100106:dicarbine; D010634:Phenobarbital