S-oxygenation of 7 alpha-thiomethylspironolactone by the flavin-containing monooxygenase.
Liver microsomes and highly purified flavin-containing monooxygenase from uninduced hogs catalyze the NADPH and oxygen-dependent S-oxygenation of 7 alpha-thiomethylspironolactone (7 alpha-TMSL), the major urinary metabolite of spironolactone, an effective antimineralocorticoid in humans. Studies on the biochemical mechanism of S-oxygenation of 7 alpha-TMSL suggests that this reaction is catalyzed exclusively by the flavin-containing monooxygenase and not by cytochrome P-450. This conclusion is based on the effects of selective cytochrome P-450 inhibitors as well as positive effectors and alternate substrates for the flavin-containing monooxygenase. The modest degree of stereoselective S-oxygenation of 7 alpha-TMSL may suggest steric inhibition of oxidation by the flavin-containing monooxygenase.
Cashman
J R
JR
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446.
Peña
S
S
D000818:Animals; D001711:Biotransformation; D005415:Flavins / Q000378:metabolism*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000378:metabolism; D013237:Stereoisomerism; D013552:Swine
D005415:Flavins; D007202:Indicators and Reagents; D013148:Spironolactone; C046564:7-thiomethylspirolactone; D009249:NADP; D006899:Mixed Function Oxygenases