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Characterization of the Human Cytochrome P450 Forms Involved in Metabolism of Tamoxifen to Its α-Hydroxy and α,4-Dihydroxy Derivatives

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School of Biomedical Sciences, University of Queensland, St. Lucia, Australia 4072, Academic Unit of Clinical Pharmacology, Division of Clinical Sciences South, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom, and Department of Medicine, University of Queensland and Department of Clinical Pharmacology, Princess Alexandra Hospital, Woolloongabba 4102, Australia
Cite this: Chem. Res. Toxicol. 2005, 18, 10, 1611–1618
Publication Date (Web):September 30, 2005
https://doi.org/10.1021/tx050140s
Copyright © 2005 American Chemical Society

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    Abstract

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    Tamoxifen is a known hepatocarcinogen in rats and is associated with an increased incidence of endometrial cancer in patients. One mechanism for these actions is via bioactivation, where reactive metabolites are generated that are capable of binding to DNA or protein. Several metabolites of tamoxifen have been identified that appear to predispose to adduct formation. These include α-hydroxytamoxifen, α,4-dihydroxytamoxifen, and α-hydroxy-N-desmethyltamoxifen. Previous studies have shown that cytochrome P450 (P450) enzymes play an important role in the biotransformation of tamoxifen. The aim of our work was to determine which P450 enzymes were capable of producing α-hydroxylated metabolites from tamoxifen. When tamoxifen (18 or 250 μM) was used as the substrate, P450 3A4, and to a lesser extent, P450 2D6, P450 2B6, P450 3A5, P450 2C9, and P450 2C19 all produced a metabolite with the same HPLC retention time as α-hydroxytamoxifen at either substrate concentration tested. This peak was well-separated from 4-hydroxy-N-desmethyltamoxifen, which eluted substantially later under the chromatographic conditions used. No α,4-dihydroxytamoxifen was detected in incubations with any of the forms with tamoxifen as substrate. However, when 4-hydroxytamoxifen (100 μM) was used as the substrate, P450 2B6, P450 3A4, P450 3A5, P450 1B1, P450 1A1, and P450 2D6 all produced detectable concentrations of α,4-dihydroxytamoxifen. These studies demonstrate that multiple human P450s, including forms found in the endometrium, may generate reactive metabolites in women undergoing tamoxifen therapy, which could subsequently play a role in the development of endometrial cancer.

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     University of Queensland.

     Royal Hallamshire Hospital.

    §

     Princess Alexandra Hospital.

    *

     To whom correspondence should be addressed. (M.S.L.) Tel:  +44-114-271 2578. Fax:  +44-114-272 0275. E-mail:  M.S.Lennard@ sheffield.ac.uk. (E.M.J.) Tel:  +61-7-3365 1410. Fax:  +61-7-3365 1766. E-mail:  [email protected].

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