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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 [ ¹⁴ C]tamoxifen to intermediates that irreversibly bind to exogenous DNA. Incubation of [ ¹⁴ C]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/10 ⁸ nucleotides (mean ± SE, n …