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Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/1688

Title: Identification of human CYP forms involved in the activation of tamoxifen and irreversible binding to DNA
Authors: Boocock, David J.
Brown, Karen
Gibbs, Anthony H.
Sanchez, Esther
Turteltaub, Kenneth W.
White, Ian N.H.
Issue Date: Nov-2002
Publisher: Oxford University Press (OUP)
Citation: Carcinogenesis, 2002, 23 (11), pp.1897-1902
Abstract: This study investigates which CYP forms are responsible for the conversion of tamoxifen to its putative active metabolite α-hydroxytamoxifen and irreversible binding to DNA. We have used eight different baculovirus expressed recombinant human CYP forms and liquid chromatography-mass spectrometry to show that only CYP3A4 is responsible for the NADPH-dependent α-hydroxylation of tamoxifen. Surprisingly, this CYP did not catalyse the formation of 4-hydroxytamoxifen. We demonstrate for the first time, by means of accelerator mass spectrometry, that CYP3A4 also catalysed the activation of [14C]tamoxifen to intermediates that irreversibly bind to exogenous DNA. Incubation of [14C]tamoxifen (20.6 kBq, 100 μM) with CYP3A4, in the presence of NADPH for 60 min led to levels of DNA binding of 39.0±9.0 adducts/108 nucleotides (mean ± SE, n = 6). While CYP3A4 converted tamoxifen to N-desmethyltamoxifen (38.3 ± 7.20 pmol/20 min/pmol CYP, n = 4), the polymorphic CYP2D6 showed the highest activity for producing this metabolite (48.6±1.52pmol/20 min/pmol CYP). CYP2D6 was also the most active in catalysing 4-hydroxylation of tamoxifen, although an order of magnitude lower level was also detected with CYP2C19. With tamoxifen as substrate, no 3,4-dihydroxytamoxifen could be detected with any CYP form. CYP2B6 did not catalyse the metabolism or the binding of tamoxifen to DNA. It is concluded that CYP3A4 is the only P450 of those tested that converts tamoxifen to α-hydroxytamoxifen and the only one that results in appreciable levels of irreversible binding of tamoxifen to DNA.
DOI Link: 10.1093/carcin/23.11.1897
ISSN: 0143-3334
Links: http://hdl.handle.net/2381/1688
Type: Article
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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