Isotope effect studies on the mechanism of the cytochrome P-450IIA1-catalyzed formation of delta 6-testosterone from testosterone.
Testosterone metabolism by cytochrome P-450IIA1 results in four metabolites: 6 alpha-hydroxytestosterone; 7 alpha-hydroxytestosterone; 17 beta-hydroxy-4,6-androstadiene-3-one (delta 6-T); and 17 beta-hydroxy-4,6-androstadiene-3-one-6,7-oxide. The epoxide is formed upon further oxidation of delta 6-T, and its formation is in competition with the dissociation of delta 6-T from the active site. The analysis of the KM and Vmax values, as well as the product ratios for testosterone and three selectively deuterated analogs, strongly suggest that delta 6-testosterone formation occurs primarily by initial hydrogen atom abstraction at the 6 alpha-position followed by abstraction of the 7 alpha-hydrogen atom.
Korzekwa
K R
KR
Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Trager
W F
WF
Nagata
K
K
Parkinson
A
A
Gillette
J R
JR
D000818:Animals; D001711:Biotransformation; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D010084:Oxidation-Reduction; D051381:Rats; D013739:Testosterone / Q000378:metabolism*
D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System