Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: Prominent roles for CYP3A and CYP2D6

Journal of Pharmacology and Experimental Therapeutics

Volumn 310, Issue 3, 2004, Pages 1062-1075

  Desta, Zeruesenay ^a   Ward, Bryan A ^a   Soukhova, Nadia V ^b   Flockhart, David A ^a  

^a INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b GEORGETOWN UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3,4 DIHYDROXYTAMOXIFEN; 4' HYDROXYTAMOXIFEN; ALPHA HYDROXY NORTAMOXIFEN; ALPHA HYDROXYTAMOXIFEN; CYTOCHROME P450; CYTOCHROME P450 2C19; CYTOCHROME P450 2D6; CYTOCHROME P450 3A; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; DROLOXIFENE; DRUG METABOLITE; ENDOXIFEN; NORTAMOXIFEN; TAMOXIFEN; TAMOXIFEN DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BIOTRANSFORMATION; CONTROLLED STUDY; CORRELATION ANALYSIS; DRUG METABOLISM; DRUG SCREENING; DRUG TRANSFORMATION; ENZYME INHIBITION; ENZYME KINETICS; ENZYME MECHANISM; ENZYME SUBSTRATE; GENETIC POLYMORPHISM; HUMAN; HUMAN TISSUE; IN VITRO STUDY; IN VIVO STUDY; LIVER MICROSOME; OXIDATION; PRIORITY JOURNAL; PROTEIN FAMILY;

BIOTRANSFORMATION; CYTOCHROME P-450 CYP2D6; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; KINETICS; MICROSOMES, LIVER; OXIDATION-REDUCTION; STATISTICS; TAMOXIFEN;

EID: 4243063941     PISSN: 00223565     EISSN: None     Source Type: Journal    
DOI: 10.1124/jpet.104.065607     Document Type: Article

References (40)

1. Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, and Sahmoud T (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359:2131-2139.
2. Borgna JL and Rochefort H (1981) Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem 256:859-868.
3. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248-254.
4. Bratherton DG, Brown CH, Buchanan R, Hall V, Kingsley Pillers EM, Wheeler TK, and Williams CJ (1984) A comparison of two doses of tamoxifen (Nolvadex) in postmenopausal women with advanced breast cancer: 10 mg bd versus 20 mg bd. Br J Cancer 50:199-205.
5. Clarke R, Leonessa F, Welch JN, and Skaar TC (2001) Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol Rev 53:25-71.
6. Coezy E, Borgna JL, and Rochefort H (1982) Tamoxifen and metabolites in MCF7 cells: correlation between binding to estrogen receptor and inhibition of cell growth. Cancer Res 42:317-323.
7. Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, Nussler A, Neuhaus P, Zanger UM, Eichelbaum M, et al. (2002) The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antiestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol 54:157-167.
8. Coller JK, Krebsfaenger N, Klein K, Wolbold R, Nussler A, Neuhaus P, Zanger UM, Eichelbaum M, and Murdter TE (2004) Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity. Br J Clin Pharmacol 57:105-111.
9. Comoglio A, Gibbs AH, White IN, Gant T, Martin EA, Smith LL, Gamalero SR, and DeMatteis F (1996) Effect of tamoxifen feeding on metabolic activation of tamoxifen by the liver of the rhesus monkey: does liver accumulation of inhibitory metabolites protect from tamoxifen-dependent genotoxicity and cancer? Carcinogenesis 17:1687-1693.
10. Crewe HK, Ellis SW, Lennard MS, and Tucker GT (1997) Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem Pharmacol 53:171-178.
11. Crewe HK, Notley LM, Wunsch RM, Lennard MS, and Gillam EM (2002) Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4′-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos 30:869-874.
12. Dehal SS and Kupfer D (1997) CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res 57:3402-3406.
13. Dehal SS and Kupfer D (1999) Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) yielding tamoxifen catechol: involvement of catechols in covalent binding to hepatic proteins. Drug Metab Dispos 27:681-688.
14. Ducharme J, Fried K, Shenouda G, Leyland-Jones B, and Wainer IW (1997) Tamoxifen metabolic patterns within a glioma patient population treated with high-dose tamoxifen. Br J Clin Pharmacol 43:189-193.
15. Early Breast Cancer Trialists' Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351:1451-1467.
16. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, et al. (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388.
17. Jacolot F, Simon I, Dreano Y, Beaune P, Riche C, and Berthou F (1991) Identification of the cytochrome P450 IIIA family as the enzymes involved in the N-demethylation of tamoxifen in human liver microsomes. Biochem Pharmacol 41:1911-1919.
18. Johnson MD, Zua H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z, Flockhart DA, Skaar TC (2004) Pharmacological characterization of 4-hydroxy N-desmethyltamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat, in press.
19. Jordan VC (1982) Metabolites of tamoxifen in animals and man: identification, pharmacology and significance. Breast Cancer Res Treat 2:123-138.
20. Jordan VC, Collins MM, Rowsby L, and Prestwich G (1977) A monohydroxylated metabolite of tamoxifen with potent antiestrogenic activity. J Endocrinol 75:305-316.
21. Kivisto KT, Villikka K, Nyman L, Anttila M, and Neuvonen PJ (1998) Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin. Clin Pharmacol Ther 64:648-654.
22. Lee KH, Ward BA, Desta Z, Flockhart DA, and Jones DR (2003) Quantification of tamoxifen and three metabolites in plasma by high-performance liquid chromatography with fluorescence detection: application to a clinical trial. J Chromatogr B Analyt Technol Biomed Life Sci 791:245-253.
23. Lien EA, Anker G, Lonning PE, Solheim E, and Ueland PM (1990) Decreased serum concentrations of tamoxifen and its metabolites induced by aminoglutethimide. Cancer Res 50:5851-58576.
24. Lien EA, Solheim E, Kvinnsland S, and Ueland PM (1988) Identification of 4-hydroxy-N-desmethyltamoxifen as a metabolite of tamoxifen in human bile. Cancer Res 48:2304-2308.
25. Lien EA, Solheim E, Lea OA, Lundgren S, Kvinnsland S, and Ueland PM (1989) Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res 49:2175-2183.
26. Lien EA, Solheim E, and Ueland PM (1991) Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Res 51:4837-4844.
27. Lim, Li L, Desta Z, Rae JM, Flockhart DA, and Skaar TC (2004) Gene expression profiles of 4-hydroxy-N-desmethyltamoxifen (endoxifen) and 4-hydroxytamoxifen (4OHTAM) treated human breast cancer cells determined by cDNA microarray analysis. Clin Pharmacol Ther 75:49.
28. Lonning PE, Lien EA, Lundgren S, and Kvinnsland S (1992) Clinical pharmacokinetics of endocrine agents used in advanced breast cancer. Clin Pharmacokinet 22:327-358.
29. Osborne CK (1998) Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609-1618.
30. Poon GK, Chui YC, McCague R, Llnning PE, Feng R, Rowlands MG, and Jarman M (1993) Analysis of phase I and phase II metabolites of tamoxifen in breast cancer patients. Drug Metab Dispos 21:1119-1124.
31. Rae JM, Soukhova NV, Flockhart DA, and Desta Z (2002) Triethylenethiophosphoramide is a specific inhibitor of cytochrome P450 2B6: implications for cyclophosphamide metabolism. Drug Metab Dispos 30:525-530.
32. Robertson DW, Katzenellenbogen JA, Long DJ, Rorke EA, and Katzenellenbogen BS (1982) Tamoxifen antiestrogens: a comparison of the activity, pharmacokinetics and metabolic activation of the cis and trans isomers of tamoxifen. J Steroid Biochem 16:1-13.
33. Roos W, Oeze L, Loser R, and Eppenberger U (1983) Antiestrogenic action of 3-hydroxytamoxifen in the human breast cancer cell line MCF-7. J Natl Cancer Inst 71:55-59.
34. Ruenitz PC, Bagley JR, and Mokler CM (1982) Estrogenic and antiestrogenic activity of monophenolic analogues of tamoxifen, (Z)-2-[p-(1,2-diphenyl-1- butenyl)phenoxy]-N, N-dimethylethylamine. J Med Chem 25:1056-1060.
35. Ruenitz PC, Bagley JR, and Pape CW (1984) Some chemical and biochemical aspects of liver microsomal metabolism of tamoxifen. Drug Metab Dispos 12:478-483.
36. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, and Flockhart DA (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758-1764.
37. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, and Desta Z (2003) The cytochrome P4502B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 306:287-300.
38. White IN (2003) Tamoxifen: is it safe? Comparison of activation and detoxication mechanisms in rodents and in humans. Curr Drug Metab 4:223-239.
39. Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, Hamman MA, Hall SD, and Wrighton SA (2002) Comparative metabolic capabilities of CYP3A4, CYP3A5 and CYP3A7. Drug Metab Dispos 30:883-891.
40. Zanger UM, Raimundo S, and Eichelbaum M (2004) Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 369:23-37.