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.
Stefek
M
M
Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Czechoslovakia.
Benes
L
L
Zelník
V
V
D000818:Animals; D000889:Anti-Arrhythmia Agents; D005415:Flavins / Q000378:metabolism*; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D000889:Anti-Arrhythmia Agents; D005415:Flavins; D009249:NADP; D008713:Methimazole; D008748:Methylcholanthrene; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; C052822:stobadine N-oxidase; D010100:Oxygen; D010634:Phenobarbital