Reductive metabolism of metyrapone by a quercitrin-sensitive ketone reductase in mouse liver cytosol.
Mouse liver cytosol catalyses the reduction of metyrapone to the corresponding alcohol metabolite metyrapol. The enzyme involved was characterized as a NADPH-dependent carbonyl reductase which is strongly inhibited by the plant flavonoid quercitrin but which shows no sensitivity to phenobarbital. Thus, by inhibitor subdivision of carbonyl reductases the metyrapone reductase in mouse liver cytosol has to be classified as a ketone reductase rather than an aldehyde reductase, as it was shown previously for the analogous enzyme in mouse liver microsomes based on the same pattern of inhibitor classification. Moreover, immunological comparison of the metyrapone reductases from the two subcellular fractions reveal no common antigenic determinants indicating the structural difference between these enzymes. In conclusion, metyrapone undergoes reductive biotransformation mediated by two clearly distinct carbonyl reductases located in different subcellular compartments of mouse liver cells. Considering the convenient and sensitive HPLC-method for direct metyrapol determination, metyrapone may serve as a useful tool in the investigation of these enzymes, although their physiological roles remain to be determined.
Maser
E
E
Department of Pharmacology and Toxicology, School of Medicine, University of Marburg, Lahn, Federal Republic of Germany.
Netter
K J
KJ
D000429:Alcohol Oxidoreductases / Q000187:drug effects*; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008797:Metyrapone / Q000031:analogs & derivatives / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology
C002196:metyrapol; C012526:quercitrin; D011794:Quercetin; D000429:Alcohol Oxidoreductases; D008797:Metyrapone