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Type: Journal article
Title: Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity
Author: Coller, J.
Krebsfaenger, N.
Klein, K.
Wolbold, R.
Nussler, A.
Neuhaus, P.
Zanger, U.
Eichelbaum, M.
Murdter, T.
Citation: British Journal of Clinical Pharmacology, 2004; 57(1):105-111
Publisher: Blackwell Publishing Ltd
Issue Date: 2004
ISSN: 0306-5251
Statement of
Janet K. Coller, Niels Krebsfaenger, Kathrin Klein, Renzo Wolbold, Andreas Nüssler, Peter Neuhaus, Ulrich M. Zanger, Michel Eichelbaum and Thomas E. Mürdter
Abstract: AIMS: To characterize the interindividual variability and the individual CYP involved in the formation of α-hydroxy-, N-desmethyl- and N-didesmethyl-tamoxifen from tamoxifen. METHODS: Microsomes from 50 human livers were used to characterize the interindividual variability in the α-hydroxylation, N-desmethylation and N-didesmethylation of tamoxifen. Selective inhibitors and recombinant enzymes were used to identify the forms of CYP catalysing these reactions. RESULTS: The rates of formation of α-hydroxy-, N-desmethyl- and N-didesmethyl-tamoxifen were highly variable, and correlated with each other (P < 0.0001). The respective ranges were 0.7–11.4, 25.7–411, and below the limit of quantification – 4.4 pmol mg1 protein min1. Formation of all metabolites was observed with expressed recombinant CYP3A4, inhibited by troleandomycin (65, 77 and 35%, respectively, P < 0.05) and associated with CYP3A4 expression (rs = 0.612, rs = 0.585 and rs = 0.430, P < 0.01, respectively). CONCLUSIONS: Formation of α-hydroxy-, N-desmethyl- and N-didesmethyl-tamoxifen in vitro is highly variable and mediated predominantly by CYP3A4.
Keywords: Microsomes, Liver
Cytochrome P-450 Enzyme System
Middle Aged
Child, Preschool
Cytochrome P-450 CYP3A
Genetic Variation
Description: The definitive version is available at
DOI: 10.1046/j.1365-2125.2003.01970.x
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