POLYMORPHISMS OF DRUG-METABOLIZING ENZYMES CYP1A2, CYP2D6, GST, NAT2 AND TRANSPORTER MDR1 IN POPULATION OF BELARUS: COMPARISON WITH SELECTED EUROPEAN AND ASIAN POPULATIONS
Abstract
Drug therapeutic efficiency and development of unfavorable pharmacologic responses as well as the disease predisposition are caused first of all by patient’s genetic features. Genetic variations in genes encoding drug-metabolizing enzymes and transporter proteins are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity of drugs. For that reason, it is necessary to establish the normative frequency distribution of genotypes and alleles of these genes in a particular population. Data on frequency of pharmacogenetic polymorphisms in the of Belarus population are limited. The goal of our investigation was to analyze the frequency distribution of genotypes and alleles of genes encoding drug-metabolizing enzymes (CYP1А2, CYP2D6 – I phase; GSTs, NAT2 – II phase) and transporter protein MDR1 in the population of Belarus and comparisons with other ethnic populations. Our results indicate that clinically important genes are genetically highly variable and differ considerably between populations. Differences in allele frequencies across continents should be considered when designing clinical trials of new drugs continents should be considered when designing clinical trials of new drugs.
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Franceschi, M., Scarcelli, C., Niro, V., Seripa, D., Pazienza, A. M., Pepe, G. et. al (2008). Prevalence, Clinical Features and Avoidability of Adverse Drug Reactions as Cause of Admission to??a??Geriatric Unit. Drug Safety, 31 (6), 545–556. doi: 10.2165/00002018-200831060-00009
Lonetti, A., Fontana, M. C., Martinelli, G., Iacobucci, I. (2016). Single Nucleotide Polymorphisms as Genomic Markers for High-Throughput Pharmacogenomic Studies. Microarray Technology, 143–159. doi: 10.1007/978-1-4939-3136-1_11
Chaudhary, R., Singh, B., Kumar, M., Gakhar, S. K., Saini, A. K., Parmar, V. S., Chhillar, A. K. (2015). Role of single nucleotide polymorphisms in pharmacogenomics and their association with human diseases. Drug Metabolism Reviews, 47( 3), 281–290. doi: 10.3109/03602532.2015.1047027
Piruzyan, L. А. (2004). Human metabolic passport – the basis of a new strategy in pharmacology. Vesti. RAN, 74, 610–618.
Ma, Q., Lu, A. Y. H. (2011). Pharmacogenetics, Pharmacogenomics, and Individualized Medicine. Pharmacological Reviews, 63 (2), 437–459. doi: 10.1124/pr.110.003533
Ono, C., Kikkawa, H., Suzuki, A., Suzuki, M., Yamamoto, Y., Ichikawa, K. et. al (2013). Clinical impact of genetic variants of drug transporters in different ethnic groups within and across regions. Pharmacogenomics, 14( 14), 1745–1764. doi: 10.2217/pgs.13.171
Daly, A. K. (2015). Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations. Drug Metabolism and Personalized Therapy, 30 (3). doi: 10.1515/dmdi-2014-0034
Ramamoorthy, A., Pacanowski, M., Bull, J., Zhang, L. (2015). Racial/ethnic differences in drug disposition and response: Review of recently approved drugs. Clinical Pharmacology & Therapeutics, 97 (3), 263–273. doi: 10.1002/cpt.61
Chakova, N. N., Mikhalenko, E. P., Polonetskaya, S. N., Chebotareva, N. V., Demidchik, Y. E., Zhilko, A. A. et. al (2009). GST polymorphism and cytogenetic changes in lung tissues of lung cancer patients. Cytology and Genetics, 43 (1), 38–41. doi: 10.3103/s0095452709010071
Samer, C. F., Lorenzini, K. I., Rollason, V., Daali, Y., Desmeules, J. A. (2013). Applications of CYP450 Testing in the Clinical Setting. Molecular Diagnosis & Therapy, 17 (3), 165–184. doi: 10.1007/s40291-013-0028-5
Ota, T., Kamada, Y., Hayashida, M., Iwao-Koizumi, K., Murata, S., Kinoshita, K. (2015). Combination Analysis in Genetic Polymorphisms of Drug-Metabolizing Enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese Population. International Journal of Medical Sciences, 12 (1), 78–82. doi: 10.7150/ijms.10263
Zhou, S.-F., Yang, L.-P., Zhou, Z.-W., Liu, Y.-H., Chan, E. (2009). Insights into the Substrate Specificity, Inhibitors, Regulation, and Polymorphisms and the Clinical Impact of Human Cytochrome P450 1A2. The AAPS Journa, 11 (3), 481–494. doi: 10.1208/s12248-009-9127-yy
Sainz, J., Rudolph, A., Hein, R., Hoffmeister, M., Buch, S., von Schonfels, W. et. al (2011). Association of genetic polymorphisms in ESR2, HSD17B1, ABCB1, and SHBG genes with colorectal cancer risk. Endocrine Related Cancer, 18 (2), 265–276. doi: 10.1530/erc-10-0264
Shimada, N., Iwasaki, M., Kasuga, Y., Yokoyama, S., Onuma, H., Nishimura, H. et. al (2009). Genetic polymorphisms in estrogen metabolism and breast cancer risk in case–control studies in Japanese, Japanese Brazilians and non-Japanese Brazilians. Journal of Human Genetics, 54 (4), 209–215. doi: 10.1038/jhg.2009.13
Li, D. (2005). Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes, smoking, and risk of pancreatic cancer. Carcinogenesis, 27 (1), 103–111. doi: 10.1093/carcin/bgi171
Watson, M. (1998). Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis, 19 (2), 275–280. doi: 10.1093/carcin/19.2.275
Cote, M. L., Wenzlaff, A. S., Bock, C. H., Land, S. J., Santer, S. K., Schwartz, D. R., Schwartz, A. G. (2007). Combinations of cytochrome P-450 genotypes and risk of early-onset lung cancer in Caucasians and African Americans: A population-based study. Lung Cancer, 55 (3), 255–262. doi: 10.1016/j.lungcan.2006.11.002
Egan, K. M. (2004). Genetic Polymorphisms in GSTM1, GSTP1, and GSTT1 and the Risk for Breast Cancer: Results from the Shanghai Breast Cancer Study and Meta-Analysis. Cancer Epidemiology Biomarkers & Prevention, 13 (2), 197–204. doi: 10.1158/1055-9965.epi-03-0294
Hein, D. W., Grant, D. M., Sim, E. (2000). Update on consensus arylamine N-acetyltransferase gene nomenclature. Pharmacogenetics, 10 (4), 291–292. doi: 10.1097/00008571-200006000-00002
Wikman, H., Thiel, S., Jäger, B., Schmezer, P., Spiegelhalder, B., Edler, L., Dienemann, H., Kayser, K., Schulz, V., Drings, P., Bartsch, H., Risch, A. (2001). Relevance of N-acetyltransferase 1 and 2 (NAT1, NAT2) genetic polymorphisms in non-small cell lung cancer susceptibility. Pharmacogenetics, 11 (2), 157–168. doi: 10.1097/00008571-200103000-00006
Boccia, S., Sayed-Tabatabaei, F. A., Persiani, R., Gianfagna, F., Rausei, S., Arzani, D. et. al (2007). Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population. BMC Cancer, 7 (1), 206. doi: 10.1186/1471-2407-7-206
Hou, S. M., Fält, S., Yang, K., Nyberg, F., Pershagen, G., Hemminki, K., Lambert, B. (2001). Differential interactions between GSTM1 and NAT2 genotypes on aromatic DNA adduct level and HPRT mutant frequency in lung cancer patients and population controls. Cancer Epidemiol Biomarkers Prev., 10 (2), 133–140.
McGrath, M., Michaud, D., De Vivo, I. (2006). Polymorphisms in GSTT1, GSTM1, NAT1 and NAT2 genes and bladder cancer risk in men and women. BMC Cancer, 6 (6), 239.
Ingelman-Sundberg, M., Sim, S. C., Gomez, A., Rodriguez-Antona, C. (2007). Influence of cytochrome P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacology & Therapeutics, 116 (3), 496–526. doi: 10.1016/j.pharmthera.2007.09.004
CYP2D6 allele nomenclature. Available at: http://www.cypalleles.ki.se/cyp2d6.htm
McGraw, J., Waller, D. (2012). Cytochrome P450 variations in different ethnic populations. Expert Opinion on Drug Metabolism & Toxicology, 8 (3), 371–382. doi: 10.1517/17425255.2012.657626
Bradford, L. D. (2002). CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics, 3 (2), 229–243. doi: 10.1517/14622416.3.2.229
Ginsberg, G., Smolenski, S., Hattis, D., Guyton, K. Z., Johns, D. O., Sonawane, B. (2009). Genetic Polymorphism in Glutathione Transferases (GST): Population Distribution of GSTM1, T1, and P1 Conjugating Activity. Journal of Toxicology and Environmental Health, Part B, 12 (5-6), 389–439. doi: 10.1080/10937400903158375
Makarova, S. (2008). Human N-Acetyltransferases and Drug-Induced Hepatotoxicity. Current Drug Metabolism, 9 (6), 538–545. doi: 10.2174/138920008784892047
Moslehi, R., Chatterjee, N., Church, T. R., Chen, J., Yeager, M., Weissfeld, J. et. al(2006). Cigarette smoking, N -acetyltransferase genes and the risk of advanced colorectal adenoma. Pharmacogenomics, 7 (6), 819–829. doi: 10.2217/14622416.7.6.819
Walraven, J., Zang, Y., Trent, J., Hein, D. (2008). Structure/Function Evaluations of Single Nucleotide Polymorphisms in Human N-Acetyltransferase 2. Current Drug Metabolism, 9 (6), 471–486. doi: 10.2174/138920008784892065
Stieger, B., Meier, P. J. (2011). Pharmacogenetics of drug transporters in the enterohepatic circulation. Pharmacogenomics, 12 (5), 611–631. doi: 10.2217/pgs.11.53
Sakaeda, T., Nakamura, T., Okumura, K. (2003). Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs. Pharmacogenomics, 4 (4), 397–410. doi: 10.1517/phgs.4.4.397.22747
Brambila-Tapia, A. J. (2013). MDR1 (ABCB1) polymorphisms: functional effects and clinical implications. Rev. Invest. Clin., 65 (5),445–454.
Ameyaw, M.-M., Regateiro, F., Li, T., Liu, X., Tariq, M., Mobarek, A. et. al (2001). MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics, 11 (3), 217–221. doi: 10.1097/00008571-200104000-00005
Jamroziak, K., Balcerczak, E., Młynarski, W., Mirowski, M., Robak, T. (2002). Distribution of allelic variants of functional C3435T polymorphism of drug transporter MDR1 gene in a sample of Polish population. Pol. J. Pharmacol., 54 (5), 495–500.
Saidijam, M., Mahjub, H., Shabab, N., Yadegarazari, R. (2015). Simultaneous analysis of multidrug resistance 1(MDR1) C3435T, G2677T/A, and C1236T genotypes in Hamadan City population, West of Iran. Iran Biomed J., 19 (1), 57–62. doi: 10.6091/ibj.1381.2014
Sakaeda, T., Nakamura, T., Horinouchi, M., Kakumoto, M., Ohmoto, N., Sakai, T. et. al (2001). MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharmaceutical Research, 18 (10), 1400–1404. doi: 10.1023/a:1012244520615
Franke, R., Gardner, E., Sparreboom, A. (2010). Pharmacogenetics of Drug Transporters. Current Pharmaceutical Design, 16 (2), 220–230. doi: 10.2174/138161210790112683
Gao, B., Yang, F. M., Yu, Z. T., Li, R., Xie, F., Chen, J. et. al (2015). Relationship between the expression of MDR1 in hepatocellular cancer and its biological behaviors. Int J Clin Exp Pathol., 8 (6), 6995–7001.
DOI: http://dx.doi.org/10.21303/2504-5695.2016.00105
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Copyright (c) 2016 Alena Mikhalenka, Natalia Chebotareva, Evelina Krupnova, Anna Shchayuk, Natalia Chakava, Svetlana Niyazava

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