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Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes.
Biochem Pharmacol. 1997 Jan 24; 53(2):171-8.BP

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 microM substrate concentration) and 6-25 pmol/mg protein/min (18 microM)]. 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 (1 microM), sulphaphenazole (20 microM) and ketoconazole (2 microM), 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.

Authors+Show Affiliations

University of Sheffield, Department of Medicine and Pharmacology, Royal, Hallamshire Hospital, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9037249

Citation

Crewe, H K., et al. "Variable Contribution of Cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of Tamoxifen By Human Liver Microsomes." Biochemical Pharmacology, vol. 53, no. 2, 1997, pp. 171-8.
Crewe HK, Ellis SW, Lennard MS, et al. Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem Pharmacol. 1997;53(2):171-8.
Crewe, H. K., Ellis, S. W., Lennard, M. S., & Tucker, G. T. (1997). Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochemical Pharmacology, 53(2), 171-8.
Crewe HK, et al. Variable Contribution of Cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of Tamoxifen By Human Liver Microsomes. Biochem Pharmacol. 1997 Jan 24;53(2):171-8. PubMed PMID: 9037249.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. AU - Crewe,H K, AU - Ellis,S W, AU - Lennard,M S, AU - Tucker,G T, PY - 1997/1/24/pubmed PY - 1997/1/24/medline PY - 1997/1/24/entrez SP - 171 EP - 8 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 53 IS - 2 N2 - 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 microM substrate concentration) and 6-25 pmol/mg protein/min (18 microM)]. 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 (1 microM), sulphaphenazole (20 microM) and ketoconazole (2 microM), 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. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/9037249/Variable_contribution_of_cytochromes_P450_2D6_2C9_and_3A4_to_the_4_hydroxylation_of_tamoxifen_by_human_liver_microsomes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(96)00650-8 DB - PRIME DP - Unbound Medicine ER -