Document Detail

Mechanism of androstenedione formation from testosterone and epitestosterone catalyzed by purified cytochrome P-450b.
MedLine Citation:
PMID:  3053709     Owner:  NLM     Status:  MEDLINE    
A purified rat hepatic monooxygenase system containing cytochrome P-450b oxidizes testosterone to androstenedione and 16 alpha- and 16 beta-hydroxytestosterone at approximately equal rates. The metabolism of epitestosterone by the same system is characterized by a marked stereoselectivity in favor of 16 beta-hydroxylation (4- to 5-fold relative to 16 alpha-hydroxylation), formation of 15 alpha-hydroxyepitestosterone, and a rate of androstenedione formation which is three to five times higher than that observed with testosterone. Apparent Km values for 16 alpha- and 16 beta-hydroxylation and androstenedione formation are 20-30 microM with either substrate. Mass spectral analysis of the androstenedione formed from [16,16-2H2]testosterone and [16,16-2H2] epitestosterone indicates essentially complete retention of deuterium, thereby ruling out a mechanism of androstenedione formation via C-16 hydroxylation followed by loss of water and rearrangement. Mass spectral analysis of the C-16 hydroxylation products from incubations of testosterone or epitestosterone in 18O2 shows essentially complete incorporation of 18O (greater than 95%). Androstenedione formed from testosterone is enriched in 18O only 2-fold (5-8%) over background, while the androstenedione formed from epitestosterone shows 84% enrichment. Kinetic experiments utilizing [17-2H]testosterone and [17-2H]epitestosterone as substrates indicate that cleavage of the C-17 carbon-hydrogen bond is involved in a rate-limiting step in the formation of androstenedione from both substrates. Taken together, our results indicate that androstenedione formation from epitestosterone proceeds exclusively through the gem-diol pathway, while androstenedione formation from testosterone may proceed through a combination of gem-diol and dual hydrogen abstraction pathways.
A W Wood; D C Swinney; P E Thomas; D E Ryan; P F Hall; W Levin; W A Garland
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  263     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1988 Nov 
Date Detail:
Created Date:  1988-12-20     Completed Date:  1988-12-20     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  17322-32     Citation Subset:  IM    
Department of Oncology, Hoffmann-La Roche Inc., Nutley, New Jersey 07110.
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MeSH Terms
Androstenedione / biosynthesis*
Aryl Hydrocarbon Hydroxylases*
Chromatography, High Pressure Liquid
Cytochrome P-450 Enzyme System / metabolism*
Epitestosterone / metabolism*
Mass Spectrometry
Microsomes, Liver / metabolism*
Radioisotope Dilution Technique
Steroid 16-alpha-Hydroxylase
Substrate Specificity
Testosterone / metabolism*
Reg. No./Substance:
10028-17-8/Tritium; 481-30-1/Epitestosterone; 58-22-0/Testosterone; 63-05-8/Androstenedione; 9035-51-2/Cytochrome P-450 Enzyme System; EC Hydrocarbon Hydroxylases; EC protein, rat; EC 16-alpha-Hydroxylase

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