Türk popülasyonunda Polisitemia vera hastalarında CYP 2D6*4 polimorfizmi

Year 2018, Volume: 31 Issue: 2, 61 - 67, 05.06.2018

Zehra Okat Kezban Uçar Çiftçi Kübra Yaman Selina Toplayıcı Elif Kurt Yavuz Taga

https://doi.org/10.5472/marumj.430790

Cited By: 1

Abstract

Amaç: Birçok çalışma, ksenobiyotiklerin biyotransformasyonundan

sorumlu enzimleri kodlayan gen polimorfizmleri ile çeşitli

kanserlere olan duyarlılık arasında bir ilişkili olduğunu göstermiştir.

Bu çalışmada temel amaç, Türk popülasyonunda sitokrom P450

(CYP) 2D6*4 polimorfizmleri ile PV insidansı arasındaki ilişkiyi

saptamaktır.

Gereç ve Yöntem: Bu araştırma makalesinde, CYP 2D6*

4 polimorfizminin analizi için 80 (PV) hastası ve 76 kontrol

örneği kullanılmıştır. Deney, polimerize zincir reaksiyonu (PZR)-

restriksiyon parça uzunluğu polimorfizmi (RFLP) methodu

kullanılarak gerçekleştirilmiştir.

Bulgular: Sonuç olarak, hastalar ve kontroller CYP 2D6*

4 yavaş metabolizör (YM) ve heterozigot hızlı metabolizör

(HM) genotip sıklığına göre karşılaştırıldıklarında, hastalardaki

YM frekansı %1.35, heterozigot HM frekansı %32.43, kontrol

grubunda ise YM frekansı %2.63, heterozigot HM frekansı %21.05

olarak tespit edilmiştir. CYP 2D6 genotiplerinin analiz sonuçları

ile hasta ve kontrollerdeki hastalık riski arasındaki korelasyon

araştırılmıştır. YM, heterozigot HM ve HM genotiplerinin PV riski

ile ilişkili olmadığı bulunmuştur (OR 0.51, 95% CI 0.04-5.71, OR

1.80, 95% CI 0.86-3.75, χ2 1.93, P: 0.164, OR 0.61, 95% CI 0.30-

1.24, χ2 1.40, P: 0.235).

Sonuç: Elde ettiğimiz sonuçlar, çalışılan popülasyonda

CYP 2D6 * 4 polimorfizminin PV etyolojisinde önemli bir rol

oynamadığını göstermiştir.

Keywords

Sitokrom P450 2D6, Genetik polimorfizm, Polisitemia vera (PV)

CYP 2D6* 4 polymorphism in Polycythemia vera patients in Turkish population

Abstract

Objective: Many studies have shown the association of

susceptibility to several cancers with gene encoding enzymes’

polymorphisms which engage in xenobiotics’ biotransformation.

In this study, the main purpose is to search the relation between

cytochrome P450 (CYP) 2D6* 4 polymorphisms and Polycythemia

vera (PV) incidence in Turkish population.

Materials and Methods: In this research article, 80

Polycthemia vera (PV) cases and 76 control samples have been

used for the analysis of CYP 2D6* 4 polymorphism. The research

has been performed by the methods of polymerase chain reaction

(PCR)-restriction fragment length polymorphism (RFLP).

Results: As a result, when patients and controls were

compared in terms of CYP 2D6* 4 poor metabolizer (PM) and

heterozygous extensive metabolizer (HEM) genotype frequency,

it has been found that the patients have 1.35% PM and 32.43%

HEM frequency, and controls have 2.63% PM and 21.05% HEM

frequency. The correlation between the results of CYP 2D6

genotype analysis and the risk of disease in patients and controls

was examined. We found that PM, HEM and extensive metabolizer

(EM) genotypes were unrelated with the risk of PV (OR 0.51, 95%

CI 0.04-5.71, OR 1.80, 95% CI 0.86-3.75, χ2 1.93, P: 0.164, OR

0.61, 95% CI 0.30-1.24, χ2 1.40, P: 0.235).

Conclusion: Our results suggested that the CYP 2D6*

4 polymorphism, in the studied population, does not play an

important role in PV etiology.

Keywords

Cytochrome P450 2D6, Genetic polymorphism, Polycythemia vera (PV)

References

• Tefferi A, Elliott M. Thrombosis in myeloproliferative disorders: Prevalence, prognostic factors, and the role of leukocytes and JAK2V617F. Semin Thromb Hemost 2007; 33:313-20. doi: 10.1055/s-2007-976165.
• Spivak JL, Barosi G, Tognoni G, et al. Chronic myeloproliferative disorders. Hematology (Am Soc Hematol Educ Program) 2003; 200-24. doi: 10.1182/ asheducation-2003.1.200.
• Tefferi A. Pathogenetic mechanisms in chronic myeloproliferative disorders: polycythemia vera, essential thrombocythemia, agnogenic myeloid metaplasia, and chronic myelogenous leukemia. Seminars in Hematology 1999; 36:3–8.
• Bilgrami S, Greenberg, B R. Polycythemia rubra vera. Semin Oncol 1995; 22:307-26.
• Samuelsson J. Survival in a patient with polycthemia vera for over thirty years: implications for treatment decisions in younger patients. Leukemia and Lymphoma 1998; 32:195-8. doi: 10.3109/10428199809059262.
• Gonzalez FJ, Tukey RH, (editors). Drug Metabolism: How Humans Cope with Exposure to Xenobiotics.” Goodman and Gilman’s the Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill, 2012.
• Guengerich FP. Cytochrome p450 and chemical toxicology. Chem Res Toxicol 2008; 21:70-83. doi: 10.1021/tx700079z.
• Bock KW, Lilienblum W, Fischer G, et al. The role of conjugation reactions in detoxication. Arch Toxicol 1987; 60:22-29.
• Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2010; 154:103-16.
• Abraham JE, Maranian MJ, Driver KE, et al. CYP 2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen. Breast Cancer Res 2010;12:R64. doi: 10.1186/bcr2629.
• Cholerton S, Daly AK, Idle JR. The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol Sci 1992; 13:434-9.
• Bertilsson L, Dahl ML, Dalén P and Al-Shurbaji A. Molecular genetics of CYP 2D6: Clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002; 53:111-22. doi: 10.1046/j.0306-5251.2001.01548.x.
• Sachse C, Brockmoller J, Bauer S, et al. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997; 60:284-95.
• Hanioka N, Kimura S, Meyer UA, et al. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934----A base change in intron 3 of a mutant CYP 2D6 allele results in an aberrant 3’ splice recognition site. Am J Hum Genet 1990; 47:994-1001.
• Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression,enzyme activities, and impact of genetic variation. Pharmacology & Therapeutics 2013; 138:103-41. doi: 10.1016/j. pharmthera.2012.12.007.
• Bertilsson L, Dahl ML, Sjo¨qvist F, et al. Molecular basis for rational megaprescribing inultrarapid hydroxylators of debrisoquine. Lancet 1993; 341:63.
• Christensen РМ, Gotzsche PC, Brosen K. The sparteine/ debrisoquine (CYP 2D6) oxidation polymorphism and the risk of lung cancer: a metaanalysis. Eur J Clin Pharmacol 1997; 51:389-93. doi: 10.1007/s002280050219.
• Taninghera M, Malacarnea D, Ugolinia A, et al. Drug metabolism polymorphisms as modulators of cancer susceptibility. Mutation Research/Reviews in Mutation Research 1999; 436:227–61.
• Preston-Martin S, Pike MC, Ross RK, et al. Increased cell division as a cause of human cancer. Cancer Res 1990; 50:7415-21.
• Schur BC, Bjerke J, Nuwayhid N, et al. Genotyping of cytochrome P450 2D6*3 and *4 mutations using conventional PCR*. Clinica Chimica Acta 2001; 308:25-31. doi: 10.1016/ S0009-8981(01)00422-3.
• Kim JW, Lee CG, Park YG, et al. Combined analysis of germline polymorphisms of p53, GSTM1, GSTT1, CYP1A1, and CYP2E1: relation to the incidence rate of cervical carcinoma. Cancer 2000; 88:2082-91. doi: 10.1002/(SICI)1097-0142(20000501)88:9<2082::AIDCNCR14> 3.0.CO;2-D.
• Morgan GJ, Smith MT. Metabolic enzyme polymorphisms and susceptibility to acute leukemia in adults. Am J Pharmacogenomics 2002; 2(2).
• Hatagima, A. Genetic polymorphisms and metabolism of endocrine disruptors in cancer susceptibility. Cad. Saúde Pública Rio de Janeiro 2002; 18:357-77.
• Anwar WA, Abdel-Rahman SZ, El-Zein RA, et al. Genetic polymorphism of GSTM1, CYP2E1 and CYP 2D6 in Egyptian bladder cancer patients. Carcinogenesis 1996; 17: 1923-29.
• Caporaso NE, Tucker MA, Hoover RN, et al. Lung cancer and the debrisoquine metabolic phenotype. J Natl Cancer Inst 1990; 82:1264-72.
• Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P4502D6 (CYP 2D6): clinical consequences, evolutionary aspects and functional diversity, The Pharmacogenomics J 2005; 5:6 – 13. doi:10.1038/ sj.tpj.6500285.
• Roddam PL, Rollinson S, Kane E, et al. Poor metabolizers at the cytochrome P450 2D6 and 2C19 loci are at increased risk of developing adult acute leukaemia, Pharmacogenetics 2000; 10:605-15.
• Worrall SF, Corrigan M, High A, et al. Susceptibility and outcome in oral cancer: preliminary data showing an association with polymorphism in cytochrome P450 CYP 2D6. Pharmacogenetics 1998; 8:433-9.
• Smith CA, Gough AC, Leigh PN, et al. Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson’s disease. Lancet 1992; 339:1375–7.
• Sarmanova J, Benesova K, Gut I, et al. Genetic polymorphisms of biotransformation enzymes in patients with Hodgkin’s and non-Hodgkin’s lymphomas. Hum Mol Genet 2001;10:1265- 73.
• Aydin-Sayitoglu M, Hatirnaz O, Erensoy N, et al. Role of CYP 2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 genes in the susceptibility to acute leukemias. Am J Hematol 2006;81:162-70. doi: 10.1002/ajh.20434.
• Sailaja K, Vishnupriya S, Surekha D, et al. Association of CYP 2D6* 4 Polymorphism with Chronic Myeloid Leukemia. Journal of Medical Sciences Research 2007; 1(1).
• Lemos MC, Cabrita FJ, Silva HA, et al. Genetic polymorphism of CYP 2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias. Carcinogenesis 1999; 20: 1225- 9.
• Tayser KE, Ehsan G, Ghonemy EE, et al. Study of genetic polymorphism of xenobiotic enzymes in acute leukemia. Blood Coagulation and Fibrionolysis 2007; 18:489-95. doi: 10.1097/MBC.0b013e3281eec930.
• Joseph T, Kusumakkumary P, Chacko P, et al. Genetic polymorphism of CYP1A1, CYP 2D6, GSTM1and GSTT1 and susceptibility to acute lymphoblasticleukaemia in Indian children. Pediatric Blood Cancer 2004; 43:560 – 67. doi: 10.1002/pbc.20074.
• Krajinovic M, Labuda D, Richer C, et al. Susceptibility to childhood acute lymphoblastic leukemia: ınfluence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. Blood 1999; 93: 1496-501.
• Marsh JCW, Choudry J, Parry-Jones N, et al. Study of the association between cytochromes P450 2D6 and 2E1 genotypes and the risk of drug and chemical induced idiosyncratic aplastic anaemia. Br J Haematol 1999; 104:266-70.
• Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemisry. Naunyn Schmiedebergs Arch Pharmacol 2004; 369:23-37. doi: 10.1007/s00210-003-0832-2.
• Alvan G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990; 39:533-7.
• Aydin M, Hatirnaz O, Erensoy N, et al. CYP 2D6 and CYP1A1 mutations in the Turkish population.Cell Biochem Funct 2005; 23:133-5. doi: 10.1002/cbf.1222.
• Koseler A, Ilcol YO, Ulus IH. Frequency of mutated allele CYP 2D6* 4 in the Turkish population. Pharmacology 2007; 79:203-06. doi: 10.1159/000100959.
• Aynacıoğlu AS, Sachse C, Bozkurt A. Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population. Clin Pharmacol Ther 1999; 66: 185-92. doi: 10.1053/cp.1999.v66.100072001.
• Sahin S, Aydogan L, Benli I, et al. Distribution of HLA-B27 and CYP 2D6* 4 mutations in the middle Black Sea area (Tokat) of Turkey. Genetics and Molecular Research 2011 10:3987-91. doi: 10.4238/2011.December.2.3
• Hardy GH. Mendelian proportions in a mixed population. Science 1908; 28:49-50. doi: 10.1126/science.28.706.49
• Rodriguez S, Gaunt TR, Day IN. Hardy–Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 2009; 169:505-14. doi: 10.1093/aje/kwn359.
• Anderson LA, Duncombe AS, Hughes M, et al. Environmental, lifestyle, and familial/ethnic factors associated with myeloproliferative neoplasms. Am J Hematol 2012 ;87:175-82. doi: 10.1002/ajh.22212.
• Ozawa S. Drug-Drug Interactions with consideration of pharmacogenetics. Yakugaku zasshi Journal of the Pharmaceutical Society of Japan. 2018;138:365-71. doi: 10.1248/yakushi.17-00191-5.
• Thota K, Prasad K, Basaveswara Rao MV. Detection of cytochrome P450 polymorphisms in breast cancer patients may ımpact on tamoxifen therapy. Asian Pac J Cancer Prev 2018 26;19:343-50. doi: 10.22034/APJCP.2018.19.2.343.