Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity
作者： Janet K. Coller , Niels Krebsfaenger , Kathrin Klein , Renzo Wolbold , Andreas Nüssler
DOI: 10.1046/J.1365-2125.2003.01970.X
关键词:
摘要: Aims To characterize the interindividual variability and individual CYP involved in formation of α-hydroxy-, N-desmethyl- N-didesmethyl-tamoxifen from tamoxifen. Methods Microsomes 50 human livers were used to α-hydroxylation, N-desmethylation N-didesmethylation tamoxifen. Selective inhibitors recombinant enzymes identify forms catalysing these reactions. Results The rates highly variable, correlated with each other (P < 0.0001). respective ranges 0.7–11.4, 25.7–411, below limit quantification – 4.4 pmol mg−1 protein min−1. Formation all metabolites was observed expressed CYP3A4, inhibited by troleandomycin (65, 77 35%, respectively, P < 0.05) associated CYP3A4 expression (rs = 0.612, rs = 0.585 rs = 0.430, P < 0.01, respectively). Conclusions vitro is variable mediated predominantly CYP3A4.
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