Pharmacogenetic features of the phase II biotransformation of tamoxifen: a systematic review

Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. The antiestrogen tamoxifen is extensively metabolized in patients to form a series of compounds with altered affinity for estrogen receptors (ERs), the primary target of this drug. Furthermore, these metabolites exhibit a range of partial agonist activity for ER in endometrium, which can lead to hyperplastic processes. Interindividual and interethnic variability of tamoxifen pharmacokinetics and pharmacodynamics is the cause of a variety of therapeutic response, mortality and survival rates. The role of enzymes for metabolism of tamoxifen I phase is actively being studied, but most researchers agree that the enzymes of the phase I and their metabolites only partially explain the mechanisms of the pathological response of patients to tamoxifen therapy. This article will focus on the sulfotransferases (SULT) and glucuronosyltransferases (UGT) - enzymes of the phase II metabolism of tamoxifen, whose family will be determined and also the clinically relevant polymorphism of the genes of these enzymes (SULT1A*2, SULT1A2*2, SULT1A2*3, UGT-48Val, UGT2B7-268Tyr, UGT2B15-523Thr).

тамоксифен, SULT1A2, SULT1A1, UGT1A4, UGT2B7, UGT2B15, рак молочной железы, фармакогеномика, фармакогенетика, tamoxifen, SULT1A1, UGT1A4, UGT2B7, UGT2B15, breast cancer, pharmacogenetics, pharmacogenomics

1. Lumachi F., Luisetto G., Basso S.M., Basso U., Brunello A., Camozzi V. Endocrine therapy of breast cancer. Curr Med Chem. 2011; 18 (4): 513-22.

2. Carlson R.W., Allred D.C., Anderson B.O., Burstein H.J., Carter W.B., Edge S.B. et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2009 Feb; 7 (2): 122-92.

3. Jones M.E., van Leeuwen F.E., Hoogendoorn W.E., Mounts M.J., Hollema H., van Boven H. et al. Endometrial cancer survival after breast cancer in relation to tamoxifen treatment: pooled results from three countries. Breast Cancer Res. 2012 Jun 12; 14 (3): R91.

4. Johnson M.D., Zuo H., Lee K.H., Trebley J.P., Rae J.M., Weatherman R.V. et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004 May; 85 (2): 151-9.

5. Gjerde J., Hauglid M., Breilid H., Lundgren S., Varhaug J.E. et al. Relationship between CYP2D6 and SULT1A1 genotypes and serum concentrations of tamoxifen and its metabolites during steady state treatment in breast cancer patients. 28th Annual San Antonio Breast Cancer Symposium. 2005. Dec 08-11; San Antonio, TX.

6. Tan S.H., Lee S.C., Goh B.C., Wong J. Pharmacogenetics in Breast Cancer Therapy. Clin Cancer Res. 2008 Dec 15; 14 (24): 8027-41.

7. Sim S.C., Ingelman-Sundberg M. The Human Cytochrome P450 (CYP) Allele Nomenclature website: a peer-reviewed database of CYP variants and their associated effect. Hum Genomics. 2010 Apr; 4 (4): 278-81.

8. Fernandez-Santander A., Gaibar M., Novillo A., Romero-Lorca A., Rubio M., Chicharro L.M. et al. Relationship between Genotypes Sult1a2 and Cyp2d6 and Tamoxifen Metabolism in Breast Cancer Patients. PLoS 0ne. 2013; 8 (7): e70183.

9. Del Rea M., Micheluccib A., Simib P., Danes R. Pharmacogenetics of anti-estrogen treatment of breast cancer. ELSEVIER: 2012. Aug.; 5(38): 442-450)

10. Hui Y., Luo L., Zhang L., Kurogi K., Zhou C., Sakakibara Y. et al. Sulfation of afimoxifene, endoxifen, raloxifene, and fulvestrant by the human cytosolic sulfotransferases (SULTs): A systematic analysis. J Pharmacol Sci. 2015 Jul; 128 (3): 144-9.

11. Nowell S., Sweeney C., Winters M. et al. Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy. J Natl Cancer Inst. 2002; 94: 1635-1640.

12. Gjerde J., Hauglid M., Breilid H., Lundgren S., Varhaug J.E., Kisanga E.R. et al. Effects of CYP2D6 and SULT1A1 genotypes including sUlT1A1 gene copy number on tamoxifen metabolism. Ann 0ncol. 2008 Jan; 19 (1): 56-61.

13. Sun D., Chen G., Dellinger R.W., Duncan K., Fang J.L., Lazarus P. Characterization of tamoxifen and 4- hydroxytamoxifen glucuronidation by human UGT1A4 variants. Breast Cancer Res. 2006; 8 (4): R50.

14. Sun D., Sharma A.K., Dellinger R.W., Blevins-Primeau A.S., Balliet R.M., Chen G. et al. Glucuronidation of active tamoxifen metabolites by the human UDP-glucuronosyltransferases (UGTs). Drug Metab Dispos. 2007 Nov; 35 (11): 2006-14.

15. Zhou J., Argikar U.A., Remmel R.P. Functional analysis of UGT1A4P24T and UGT1A4L48V variant enzymes. Pharmacogenomics. 2011 Dec; 12 (12): 1671-9.

16. Romero-Lorca A., Novillo A., Gaibar M., Bandr s F., Fernandez-Santander A. Impacts of the Glucuronidase Genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on Tamoxifen Metabolism in Breast Cancer Patients. PLoS One. 2015 Jul 15; 10 (7): e0132269.

17. Mürdter T.E., Schroth W., Bacchus-Gerybadze L., Winter S., Heinkele G., Simon W. et al. Activity Levels of Tamoxifen Metabolites at the Estrogen Receptor and the Impact of Genetic Polymorphisms of Phase I and II Enzymes on Their Concentration Level Plasma. Clin Pharmacol Ther. 2011; 89: 708-717.

18. Sutiman N., Lim J.S., Muerdter T.E., Singh O., Cheung Y.B., Ng R.C. et al. Pharmacogenetics of UGT1A4, UGT2B7 and UGT2B15 and Their Influence on Tamoxifen Disposition in Asian Breast Cancer Patients. Clin Pharmacokinet. 2016 Oct; 55 (10): 1239-50.

19. Lazarus P., Blevins-Primeau A.S., Zheng Y., Sun D. Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen. Ann N Y Acad Sci. 2009 Feb; 1155: 99-111.

20. Blevins-Primeau A.S., Sun D., Chen G., Sharma A.K., Gallagher C.J., Amin S. et al. Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites. Cancer Res. 2009; 69: 1892-900.

21. Chen F., Ritter J.K., Wang M.G., McBride O.W., Lubet R.A., Owens I.S. Characterization of a cloned human dihydrotestosterone/androstanediol UDP-glucuronosyltransferase and its comparison to other steroid isoforms. Biochemistry. 1993; Oct 12; 32 (40): 10648-57.

22. Court M.H., Hao Q., Krishnaswamy S., Bekaii-Saab T., Al-Rohaimi A., von Moltke L.L. UDP-glucuronosyltransferase (UGT) 2B15 pharmacogenetics: UGT2B15 D85Y genotype and gender are major determinants of oxazepam glucuronidation by human liver. JPET. 2004: 310: 656-665.