Elsevier

Biochemical Pharmacology

Volume 53, Issue 2, 24 January 1997, Pages 171-178
Biochemical Pharmacology

Research paper
Variable contribution of cytochromes p450 2d6, 2c9 and 3a4 to the 4-hydroxylation of tamoxifen by human liver microsomes

https://doi.org/10.1016/S0006-2952(96)00650-8Get rights and content

Abstract

4-Hydroxylation is an important pathway of tamoxifen metabolism because the product of this reaction is intrinsically 100 times more potent as an oestrogen receptor antagonist than is the parent drug. Although tamoxifen 4-hydroxylation is catalysed by human cytochrome P450 (CYP), data conflict on the specific isoforms responsible. The aim of this study was to define unequivocally the role of individual CYPs in the 4-hydroxylation of tamoxifen by human liver microsomes. Microsomes from each of 10 human livers catalysed the reaction [range = 0.6–2.9 pmol/mg protein/min (1 μM substrate concentration) and 6–25 pmol/mg protein/min (18 μM)]. Three of the livers with the lowest tamoxifen 4-hydroxylation activity were from genetically poor metabolisers with respect to CYP2D6. Inhibition of activity by quinidine (1μM), sulphaphenazole (20 μM) and ketoconazole (2 μM), selective inhibitors of CYPs 2D6, 2C9 and 3A4, respectively, was 0–80%, 0–80% and 12–57%. The proportion of activity inhibited by quinidine correlated positively with total microsomal tamoxifen 4-hydroxylation activity (rs = 0.89, P < 0.01), indicating a major involvement of CYP2D6 in this reaction. Recombinant human CYPs 2D6, 2C9 and 3A4 but not CYPs 1A1, 1A2, 2C19 and 2E1 displayed significant 4-hydroxylation activity. Similar inhibition and correlation experiments confirmed that tamoxifen N-demethylation is catalysed predominantly by CYP3A4. These findings indicate that the 4-hydroxylation of tamoxifen is catalysed almost exclusively by CYPs 2D6, 2C9 and 3A4 in human liver microsomes. However, the marked between-subject variation in the contribution of these isoforms underlines the need to study metabolic reactions in a sufficient number of livers that are characterised with respect to a range of cytochrome P450 activities.

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    • Sulfation of afimoxifene, endoxifen, raloxifene, and fulvestrant by the human cytosolic sulfotransferases (SULTs): A systematic analysis

      2015, Journal of Pharmacological Sciences
      Citation Excerpt :

      Both Phase I and Phase II enzymes have been reported to be involved in the metabolism of these drugs. Tamoxifen has been shown to be metabolized to N-desmethyltamoxifen by CYP3A enzymes (10) and to 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen by CYP2D6 (11,12). These latter tamoxifen metabolites could be further subjected to sulfation and glucurnidation (13).

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    This work was partly supported by the Commission of the European Communities (contract BMH1-CT 94-1622).

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