Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity

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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 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 (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.

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