The metabolism of tamoxifen by human cytochromes P450 is rationalized by molecular modelling of the enzyme-substrate interactions: potential importance to its proposed anti-carcinogenic/carcinogenic actions.

A molecular modelling study on the human cytochrome P450-mediated metabolism of tamoxifen is reported. Using three-dimensional models of human P450s constructed from the bacterial crystal structure template, P450bm3 (CYP102), the likely mode of substrate binding is demonstrated, which is consistent with the known positions of metabolism in tamoxifen. In particular, the CYP102-derived structures of CYP3A4, CYP2D6 and CYP2C9 are able to rationalize the routes of tamoxifen metabolism reported in human subjects. The implications for potential toxicity of tamoxifen in man is discussed in the light of these findings.