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Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity
Author(s) -
Coller Janet K.,
Krebsfaenger Niels,
Klein Kathrin,
Wolbold Renzo,
Nüssler Andreas,
Neuhaus Peter,
Zanger Ulrich M.,
Eichelbaum Michel,
Mürdter Thomas E.
Publication year - 2004
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2003.01970.x
Subject(s) - tamoxifen , cyp3a4 , hydroxylation , cyp2d6 , pharmacology , microsome , in vitro , cytochrome p450 , chemistry , antiestrogen , endocrinology , medicine , biology , enzyme , metabolism , biochemistry , cancer , breast cancer
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 mg −1 protein min −1 . 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 ( r s = 0.612, r s = 0.585 and r s = 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.