QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.104.003327v1 33/6/714    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Choi, M. H. Articles by Tannenbaum, S. R. Search for Related Content PubMed PubMed Citation Articles by Choi, M. H. Articles by Tannenbaum, S. R.

CHARACTERIZATION OF TESTOSTERONE 11ß-HYDROXYLATION CATALYZED BY HUMAN LIVER MICROSOMAL CYTOCHROMES P450

Biological Engineering Division (M.H.C., P.L.S., J.S.W., S.R.T.), and Department of Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts

A combination of accelerator mass spectrometry (AMS) and liquid chromatography-tandem mass spectrometry 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 1ß-, 2-/ß-, 6ß-, 15ß-, and 16ß-hydroxytestosterones, mainly catalyzed by cytochromes P450 2C9, 2C19, and 3A4. We now report the first determination that 11ß-hydroxytestosterone (11ß-OHT) can also be formed by human liver microsomal fractions. The structures of five hydroxylated metabolites of testosterone (2ß-, 6ß-, 11ß-, 15ß-, and 16ß-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 high-performance liquid chromatography-AMS analysis of incubations of [4-¹⁴C]testosterone with human liver microsomes. 6ß-Hydroxylation was always the dominant metabolic pathway, but 2ß-, 15ß-, and 16ß-OHT, and androstenedione were also formed. The previously undetected hydroxytestosterone, 11ß-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. 11ß-Hydroxylation was inhibited by ketoconazole (IC₅₀ = 30 nM) at concentrations similar to the IC₅₀ (36 nM) for 6ß-hydroxylation Therefore, CYP3A4 could be mainly responsible for testosterone 11ß-hydroxylation in the human liver. These findings identify human hepatic biotransformation of testosterone to 11ß-OHT as a previously unrecognized extra-adrenal metabolic pathway.

This article has been cited by other articles:

				S. K. Balani, N. V. Nagaraja, M. G. Qian, A. O. Costa, J. S. Daniels, H. Yang, P. R. Shimoga, J.-T. Wu, L.-S. Gan, F. W. Lee, et al. EVALUATION OF MICRODOSING TO ASSESS PHARMACOKINETIC LINEARITY IN RATS USING LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY Drug Metab. Dispos., March 1, 2006; 34(3): 384 - 388. [Abstract] [Full Text] [PDF]