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© 1996 Oxford University Press

research-article

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

Helen Wiseman and David F.V. Lewis 1

Department of Nutrition and Dietetics, School of Life, Basic Medical and Health Sciences king's College London, Campden Hill Road, London W8 7AH
1Molecular Toxicology Group. School of Biological Sciences, University of Surrey Guildford, Surrey GU2 5XH, UK

1To whom correspondence should be addressed

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 demon-strated, 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.


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