Formation of two metyrapone N-oxides by rat liver microsomes.
In the presence of phenobarbital-pretreated rat liver microsomes and under oxidative conditions, metyrapone is transformed in vitro into reduced metyrapone and two other metabolites. In an effort to further characterize those metabolites, large-scale incubations of metyrapone were performed. Untransformed substrate and metabolites were extracted into chloroform under alkaline conditions and separated by thin-layer chromatography. The nature of the metabolites as N-oxides located on either pyridine ring was established by physical methodologies, mainly electron-impact and chemical-ionization mass spectrometry, and also by chemical reactions with titanous chloride. The formation of both N-oxides was increased in microsomes from phenobarbital-, but not from 3-methylcholanthrene-pretreated animals. N-Oxide formation during metyrapone metabolism might be an important step in its inhibitory action on the cytochrome P-450-mediated drug metabolism.
D000818:Animals; D003497:Cyclic N-Oxides / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008748:Methylcholanthrene / Q000494:pharmacology; D008797:Metyrapone / Q000031:analogs & derivatives* / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D003497:Cyclic N-Oxides; D009249:NADP; D008748:Methylcholanthrene; C020775:metyrapone N-oxide; D010634:Phenobarbital; D008797:Metyrapone