Functional characterization of wild-type and 49 CYP2D6 allelic variants for N-desmethyltamoxifen 4-hydroxylation activity

Drug Metabolism and Pharmacokinetics

Volumn 29, Issue 5, 2014, Pages 360-366

  Muroi, Yuka ^a   Saito, Takahiro ^a   Takahashi, Masamitsu ^a   Sakuyama, Kanako ^b   Niinuma, Yui ^a   Ito, Miyabi ^a   Tsukada, Chiharu ^a   Ohta, Kiminori ^b   Endo, Yasuyuki ^b   Oda, Akifumi ^c   Hirasawa, Noriyasu ^a   Hiratsuka, Masahiro ^a  

^a TOHOKU UNIVERSITY   (Japan)

^b TOHOKU PHARMACEUTICAL UNIVERSITY   (Japan)

^c KANAZAWA UNIVERSITY   (Japan)

Author keywords

CYP2D6; Cytochrome P450; Drug metabolism; Genetic polymorphisms; Pharmacogenomics; Tamoxifen

Indexed keywords

BUFURALOL; CYTOCHROME P450 2D6; NORTAMOXIFEN; N-DESMETHYLTAMOXIFEN; TAMOXIFEN;

AMINO ACID SUBSTITUTION; ARTICLE; CATALYSIS; CLEARANCE; CONTROLLED STUDY; COS 7 CELL LINE; DEMETHYLATION; ENZYME ACTIVITY; GENETIC VARIABILITY; HUMAN; HUMAN CELL; HYDROXYLATION; IN VITRO STUDY; KINETICS; LIMIT OF DETECTION; METABOLITE; PROTEIN EXPRESSION; WILD TYPE; ALLELE; ANALOGS AND DERIVATIVES; ANIMAL; BIOCATALYSIS; CHEMISTRY; CHLOROCEBUS AETHIOPS; COS 1 CELL LINE; GENETICS; METABOLISM; MOLECULAR CLONING;

ALLELES; ANIMALS; BIOCATALYSIS; CERCOPITHECUS AETHIOPS; CLONING, MOLECULAR; COS CELLS; CYTOCHROME P-450 CYP2D6; GENETIC VARIATION; HUMANS; HYDROXYLATION; KINETICS; TAMOXIFEN;

EID: 84908241988     PISSN: 13474367     EISSN: 18800920     Source Type: Journal    
DOI: 10.2133/dmpk.DMPK-14-RG-014     Document Type: Article

References (42)

1. Zanger, U. M., Raimundo, S. and Eichelbaum, M.: Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedeberg's Arch. Pharmacol., 369: 23-37 (2004).
2. Kirchheiner, J., Nickchen, K., Bauer, M., Wong, M. L., Licinio, J., Roots, I. and Brockmoller, J.: Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol. Psychiatry, 9: 442-473 (2004).
3. Gasche, Y., Daali, Y., Fathi, M., Chiappe, A., Cottini, S., Dayer, P. and Desmeules, J.: Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N. Engl. J. Med., 351: 2827-2831 (2004).
4. Goetz, M. P., Knox, S. K., Suman, V. J., Rae, J. M., Safgren, S. L., Ames, M. M., Visscher, D. W., Reynolds, C., Couch, F. J., et al.: The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res. Treat., 101: 113-121 (2007).
5. Rae, J. M.: CYP2D6 genotype should not be used to determine endocrine therapy in postmenopausal breast cancer patients. Clin. Pharmacol. Ther., 94: 183-185 (2013).
6. Ratain, M. J., Nakamura, Y. and Cox, N. J.: CYP2D6 genotype and tamoxifen activity: understanding interstudy variability in methodological quality. Clin. Pharmacol. Ther., 94: 185-187 (2013).
7. Schroth, W., Antoniadou, L., Fritz, P., Schwab, M., Muerdter, T., Zanger, U. M., Simon, W., Eichelbaum, M. and Brauch, H.: Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J. Clin. Oncol., 25: 5187-5193 (2007).
8. Schroth, W., Goetz, M. P., Hamann, U., Fasching, P. A., Schmidt, M., Winter, S., Fritz, P., Simon, W., Suman, V. J., et al.: Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA, 302: 1429-1436 (2009).
9. Desta, Z., Ward, B. A., Soukhova, N. V. and Flockhart, D. A.: Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J. Pharmacol. Exp. Ther., 310: 1062-1075 (2004).
10. Borgna, J. L. and Rochefort, H.: Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J. Biol. Chem., 256: 859-868 (1981).
11. Johnson, M. D., Zuo, H., Lee, K. H., Trebley, J. P., Rae, J. M., Weatherman, R. V., Desta, Z., Flockhart, D. A. and Skaar, T. C.: Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res. Treat., 85: 151-159 (2004).
12. Lien, E. A., Solheim, E., Lea, O. A., Lundgren, S., Kvinnsland, S. and Ueland, P. M.: Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res., 49: 2175-2183 (1989).
13. Jin, Y., Desta, Z., Stearns, V., Ward, B., Ho, H., Lee, K. H., Skaar, T., Storniolo, A. M., Li, L., et al.: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J. Natl. Cancer Inst., 97: 30-39 (2005).
14. Stearns, V., Johnson, M. D., Rae, J. M., Morocho, A., Novielli, A., Bhargava, P., Hayes, D. F., Desta, Z. and Flockhart, D. A.: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J. Natl. Cancer Inst., 95: 1758-1764 (2003).
15. Borges, S., Desta, Z., Li, L., Skaar, T. C., Ward, B. A., Nguyen, A., Jin, Y., Storniolo, A. M., Nikoloff, D. M., et al. : Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin. Pharmacol. Ther., 80: 61-74 (2006).
16. Nowell, S. A., Ahn, J., Rae, J. M., Scheys, J. O., Trovato, A., Sweeney, C., MacLeod, S. L., Kadlubar, F. F. and Ambrosone, C. B.: Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res. Treat., 91 : 249-258 (2005).
17. Seruga, B. and Amir, E.: Cytochrome P450 2D6 and outcomes of adjuvant tamoxifen therapy: results of a meta-analysis. Breast Cancer Res. Treat., 122 : 609-617 (2010).
18. Wegman, P., Elingarami, S., Carstensen, J., Stal, O., Nordenskjold, B. and Wingren, S.: Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res., 9: R7 (2007).
19. Kiyotani, K., Mushiroda, T., Hosono, N., Tsunoda, T., Kubo, M., Aki, F., Okazaki, Y., Hirata, K., Takatsuka, Y., et al.: Lessons for pharmacogenomics studies: association study between CYP2D6 genotype and tamoxifen response. Pharmacogenet. Genomics, 20: 565-568 (2010).
20. Lash, T. L., Lien, E. A., Sorensen, H. T. and Hamilton-Dutoit, S.: Genotype-guided tamoxifen therapy: time to pause for reflection? Lancet Oncol., 10: 825-833 (2009).
21. Shen, H., He, M. M., Liu, H., Wrighton, S. A., Wang, L., Guo, B. and Li, C.: Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab. Dispos., 35: 1292-1300 (2007).
22. Kiyotani, K., Mushiroda, T., Imamura, C. K., Hosono, N., Tsunoda, T., Kubo, M., Tanigawara, Y., Flockhart, D. A., Desta, Z., et al.: Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J. Clin. Oncol., 28: 1287-1293 (2010).
23. Hiratsuka, M.: In vitro assessment of the allelic variants of cytochrome P450. Drug Metab. Pharmacokinet., 27: 68-84 (2012).
24. Detsi, A., Koufaki, M. and Calogeropoulou, T.: Synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1butenyl]-phenoxyacetic acid. J. Org. Chem., 67: 4608-4611 (2002).
25. Yu, D. D. and Forman, B. M.: Simple and efficient production of (Z)-4-hydroxytamoxifen, a potent estrogen receptor modulator. J. Org. Chem., 68: 9489-9491 (2003).
26. Lee, K. H., Ward, B. A., Desta, Z., Flockhart, D. A. and Jones, D. R.: 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 (2003).
27. Marcucci, K. A., Pearce, R. E., Crespi, C., Steimel, D. T., Leeder, J. S. and Gaedigk, A.: Characterization of cytochrome P450 2D6.1 (CYP2D6.1), CYP2D6.2, and CYP2D6.17 activities toward model CYP2D6 substrates dextromethorphan, bufuralol, and debrisoquine. Drug Metab. Dispos., 30: 595-601 (2002).
28. Sakuyama, K., Sasaki, T., Ujiie, S., Obata, K., Mizugaki, M., Ishikawa, M. and Hiratsuka, M.: Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47-51, 53-55, and 57). Drug Metab. Dispos., 36: 2460-2467 (2008).
29. Yamazaki, S., Sato, K., Suhara, K., Sakaguchi, M., Mihara, K. and Omura, T.: Importance of the proline-rich region following signal-anchor sequence in the formation of correct conformation of microsomal cytochrome P-450s. J. Biochem., 114: 652-657 (1993).
30. Johansson, I., Oscarson, M., Yue, Q. Y., Bertilsson, L., Sjoqvist, F. and Ingelman-Sundberg, M.: Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol. Pharmacol., 46: 452-459 (1994).
31. Nakamura, K., Ariyoshi, N., Yokoi, T., Ohgiya, S., Chida, M., Nagashima, K., Inoue, K., Kodama, T., Shimada, N., et al.: CYP2D6.10 present in human liver microsomes shows low catalytic activity and thermal stability. Biochem. Biophys. Res. Commun., 293: 969-973 (2002).
32. Ebisawa, A., Hiratsuka, M., Sakuyama, K., Konno, Y., Sasaki, T. and Mizugaki, M.: Two novel single nucleotide polymorphisms (SNPs) of the CYP2D6 gene in Japanese individuals. Drug Metab. Pharmacokinet., 20: 294-299 (2005).
33. Kiyotani, K., Mushiroda, T., Sasa, M., Bando, Y., Sumitomo, I., Hosono, N., Kubo, M., Nakamura, Y. and Zembutsu, H.: Impact of CYP2D6∗10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci., 99: 995-999 (2008).
34. Lim, H. S., Ju Lee, H., Seok Lee, K., Sook Lee, E., Jang, I. J. and Ro, J.: Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J. Clin. Oncol., 25: 3837-3845 (2007).
35. Hoskins, J. M., Carey, L. A. and McLeod, H. L.: CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat. Rev. Cancer, 9: 576-586 (2009).
36. Stearns, V. and Rae, J. M.: Pharmacogenetics and breast cancer endocrine therapy: CYP2D6 as a predictive factor for tamoxifen metabolism and drug response? Expert Rev. Mol. Med., 10: e34 (2008).
37. Yu, A., Kneller, B. M., Rettie, A. E. and Haining, R. L.: Expression, purification, biochemical characterization, and comparative function of human cytochrome P450 2D6.1, 2D6.2, 2D6.10, and 2D6.17 allelic isoforms. J. Pharmacol. Exp. Ther., 303: 1291-1300 (2002).
38. Flanagan, J. U., Marechal, J. D., Ward, R., Kemp, C. A., McLaughlin, L. A., Sutcliffe, M. J., Roberts, G. C., Paine, M. J. and Wolf, C. R.: Phe120 contributes to the regiospecificity of cytochrome P450 2D6: mutation leads to the formation of a novel dextromethorphan metabolite. Biochem. J., 380: 353-360 (2004).
39. Keizers, P. H., Lussenburg, B. M., de Graaf, C., Mentink, L. M., Vermeulen, N. P. and Commandeur, J. N.: Influence of phenylalanine 120 on cytochrome P450 2D6 catalytic selectivity and regiospecificity: crucial role in 7-methoxy-4-(aminomethyl)-coumarin metabolism. Biochem. Pharmacol., 68: 2263-2271 (2004).
40. Fukuda, T., Nishida, Y., Imaoka, S., Hiroi, T., Naohara, M., Funae, Y. and Azuma, J.: The decreased in vivo clearance of CYP2D6 substrates by CYP2D6∗10 might be caused not only by the low-expression but also by low affinity of CYP2D6. Arch. Biochem. Biophys., 380: 303-308 (2000).
41. Gaedigk, A., Bradford, L. D., Alander, S. W. and Leeder, J. S.: CYP2D6∗36 gene arrangements within the cyp2d6 locus: association of CYP2D6∗36 with poor metabolizer status. Drug Metab. Dispos., 34: 563-569 (2006).
42. Wang, D., Poi, M. J., Sun, X., Gaedigk, A., Leeder, J. S. and Sadee, W.: Common CYP2D6 polymorphisms affecting alternative splicing and transcription: long-range haplotypes with two regulatory variants modulate CYP2D6 activity. Hum. Mol. Genet., 23: 268-278 (2014).