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Drug Metabolism and Disposition Fast Forward
First published on March 11, 2005; DOI: 10.1124/dmd.104.003327

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Man Ho Choi
Paul L Skipper
John S Wishnok
Steven R Tannenbaum
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Received for publication December 15, 2004.
Revised March 2, 2005.
Accepted for publication March 3, 2005.

Characterization of testosterone 11{beta}-hydroxylation catalyzed by human-liver microsomal cytochromes P450

Man Ho Choi 1, Paul L Skipper 1, John S Wishnok 1, Steven R Tannenbaum 1*

1 MIT

* Address correspondence to: E-mail: srt{at}mit.edu

Abstract

A combination of Accelerator Mass Spectrometry (AMS) and LC-MS/MS has been used to clarify some new aspects of testosterone metabolism. The main pathway of testosterone oxidative metabolism by human liver microsomes is the formation of 1{beta}-, 2{alpha}-/{beta}-, 6{beta}-, 15{beta}- and 16{beta}-hydroxytestosterones, mainly catalyzed by cytochromes P450 2C9, 2C19, and 3A4. We now report the first determination that 11{beta}-hydroxytestosterone (11{beta}-OHT) can also be formed by human liver microsomal fractions. The structures of five hydroxylated metabolites of testosterone (2{beta}, 6{beta}, 11{beta}, 15{beta}, and 16{beta}-OHT) and the C-17 oxidative metabolite androstenedione were determined by liquid chromatography with UV detection at 240 nm and liquid chromatography-tandem mass spectrometry. Corresponding results were obtained by HPLC-AMS analysis of incubations of [4-14C] testosterone with human liver microsomes. 6{beta}-Hydroxylation was always the dominant metabolic pathway, but 2{beta}-, 15{beta}-, and 16{beta}-OHT, and androstenedione were also formed. The previously undetected hydroxytestosterone, 11{beta}-OHT, was found to be a minor metabolite formed by human liver microsomal enzymes. It was formed more readily by CYP3A4 than by either CYP2C9 or CYP2C19. 11{beta}-Hydroxylation was inhibited by ketoconazole (IC50 = 30 nM) at concentrations similar to the IC50 (36 nM) for 6{beta}-hydroxylation Therefore, CYP3A4 could be mainly responsible for testosterone 11{beta}-hydroxylation in the human liver. These findings identify human hepatic biotransformation of testerone to 11{beta}-OHT as a previously unrecognized extra-adrenal metabolic pathway.


Key words: analytical chemistry, drug disposition, liver microsomes, metabolite identification, steroids


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