Genotype and phenotype polymorphisms of NAT2 and CYP2E1 in the Han Chinese pediatric population
LIU Fang, MIAO Qing, JIAO Wei-Wei, XIAO Jing, SUN Lin, SHEN Chen, WU Xi-Rong, SHEN Dan, YIN Qing-Qin, SHEN A-Dong
National Key Laboratory of Major Diseases in Children and Key Discipline of Pediatrics (Capital Medical University); Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China. shenad@sohu.com
Abstract OBJECTIVE: N-acetyltransferase 2 (NAT2) and cytochrome P450 2EI (CYP2E1) play a crucial role in the drug metabolic process. The aim of this study was to understand the genotype and phenotype polymorphisms of NAT2 and CYP2E1 in the Han Chinese pediatric population in order to provide a theoretical basis for individualized drug treatment. METHODS: A total of 341 (211 males and 130 females) randomly sampled Han Chinese children, aged from 2 months to 14 years, were enrolled in this study. Genotyping was carried out by PCR method, and metabolic phenotypes were identified. RESULTS: In this study population, wild genotype was found as a major genotype in seven SNPs of NAT2, rs1801279, rs1041983, rs1801280, rs1799929, rs1799930, rs1208 and rs1799931. The frequency of NAT2 fast metabolism was highest (61.3%), followed by middle to slow metabolism (34.1%). Wild genotype also predominated in the four SNPs of CYP2E1 (rs2031920, rs3813867, rs6413432 and rs72559720) named as CYP2E1*5, *6 and *2, with a frequency of 61.3%, 60.1% and 99.4% respectively. As the relationship between CYP2E1 genotype and phenotype was unknown, phenotyping of CYP2E1 was not done. CONCLUSIONS: The important SNPs of NAT2 and CYP2E1 are predominantly wild genotype in the Han Chinese pediatric population. Fast metabolic phenotype predominates in important SNPs of NAT2.
LIU Fang,MIAO Qing,JIAO Wei-Wei et al. Genotype and phenotype polymorphisms of NAT2 and CYP2E1 in the Han Chinese pediatric population[J]. 中国当代儿科杂志, 2012, 14(5): 353-358.
LIU Fang,MIAO Qing,JIAO Wei-Wei et al. Genotype and phenotype polymorphisms of NAT2 and CYP2E1 in the Han Chinese pediatric population[J]. CJCP, 2012, 14(5): 353-358.
［1］Crettol S, Petrovic N, Murray M. Pharmacogenetics of phase I and phase II drug metabolism［J］. Curr Pharm Des, 2010,16(2): 204-219.
［2］Sharifzadeh M, Rasoulinejad M, Valipour F, Nouraie M, Vaziri S. Evaluation of patientrelated factors associated with causality, preventability, predictability and severity of hepatotoxicity during antituberculosis ［correction of antituberclosis］ treatment［J］. Pharmacol Res, 2005, 51(4): 353-358.
［3］Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment［J］. Am J Respir Crit Care Med, 2002, 166(7): 916-919.
［4］Ingelman-Sundberg M, Rodriguez-Antona C. Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy［J］. Philos Trans R Soc Lond B Biol Sci, 2005, 360(1460): 1563-1570.
［5］Watanabe J, Hayashi S, Kawajiri K. Different regulation and expression of the human CYP2E1 gene due to the RsaI polymorphism in the 5'-flanking region［J］. J Biochem, 1994, 116(2): 321-326.
［6］Kawajiri K, Fujii-Kuriyama Y. P450 and human cancer［J］. Jpn J Cancer Res, 1991, 82(12): 1325-1335.
［7］Hu Y, Oscarson M, Johansson I, Yue QY, Dahl ML, Tabone M, et al. Genetic polymorphism of human CYP2E1: characterization of two variant alleles［J］. Mol Pharmacol, 1997, 51(3): 370-376.
［9］Parkin DP, Vandenplas S, Botha FJ, Vandenplas ML, Seifart HI, van Helden PD, et al. Trimodality of isoniazid elimination: phenotype and genotype in patients with tuberculosis［J］. Am J Respir Crit Care Med, 1997, 155(5): 1717-1722.
［10］Shenfield GM. Genetic polymorphisms, drug metabolism and drug concentrations［J］. Clin Biochem Rev, 2004, 25(4): 203-206.
［11］Isaza C, Henao J, Martinez JH, Sepulveda Arias JC, Beltran L. Phenotype-genotype analysis of CYP2C19 in Colombian mestizo individuals［J］. BMC Clin Pharmacol, 2007, 7: 6.
［12］Sabbagh A, Langaney A, Darlu P, Gérard N, Krishnamoorthy R, Poloni ES. Worldwide distribution of NAT2 diversity: Implications for NAT2 evolutionary history［J］. BMC Genet, 2008, 9: 21.
［13］Carriere V, Berthou F, Baird S, Belloc C, Beaune P, de Waziers I. Human cytochrome P450 2E1 (CYP2E1): from genotype to phenotype［J］. Pharmacogenetics, 1996, 6(3): 203-211.
［14］Powell H, Kitteringham NR, Pirmohamed M, Smith DA, Park B K. Expression of cytochrome P4502E1 in human liver: assessment by mRNA, genotype and phenotype［J］. Pharmacogenetics, 1998, 8(5): 411-421.
［15］Lucas D, Ferrara R, Gonzales E, Albores A, Manno M, Berthou F. Cytochrome CYP2E1 phenotyping and genotyping in the evaluation of health risks from exposure to polluted environments［J］. Toxicol Lett, 2001, 124(1-3): 71-81.
［16］Haufroid V, Buchet JP, Gardinal S, Lison D. Cytochrome P4502E1 phenotyping by the measurement of the chlorzoxazone metabolic ratio: assessment of its usefulness in workers exposed to styrene［J］. Int Arch Occup Environ Health, 2002, 75(7): 453-458.
［17］Fukino K, Sasaki Y, Hirai S, Nakamura T, Hashimoto M, Yamagishi F, et al. Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients［J］. J Toxicol Sci, 2008, 33(2): 187-195.
［18］Roy B, Chowdhury A, Kundu S, Santra A, Dey B, Chakraborty M, et al. Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 'null' mutation［J］. J Gastroenterol Hepatol, 2001, 16(9): 1033-1037.
［19］Leiro V, Fernandez-Villar A, Valverde D, Constenla L, Vazquez R, Pineiro L, et al. Influence of glutathione S-transferase M1 and T1 homozygous null mutations on the risk of antituberculosis drug-induced hepatotoxicity in a Caucasian population［J］. Liver Int, 2008, 28(6): 835-839.
［20］Huang YS, Su WJ, Huang YH, Chen CY, Chang FY, Lin HC, et al. Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H: quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to druginduced liver injury［J］. J Hepatol, 2007, 47(1): 128-134.
［21］Hildesheim A, Anderson LM, Chen CJ, Cheng YJ, Brinton LA, Daly AK, et al. CYP2E1 genetic polymorphisms and risk of nasopharyngeal carcinoma in Taiwan［J］. J Natl Cancer Inst, 1997, 89(16): 1207-1212.
［22］Sugimura T, Kumimoto H, Tohnai I, Fukui T, Matsuo K, Tsurusako S, et al. Gene-environment interaction involved in oral carcinogenesis: molecular epidemiological study for metabolic and DNA repair gene polymorphisms［J］. J Oral Pathol Med, 2006, 35(1): 11-18.
［23］Liu R, Yin LH, Pu YP. Association of combined CYP2E1 gene polymorphism with the risk for esophageal squamous cell carcinoma in Huai'an population, China［J］. Chin Med J (Engl), 2007, 120(20): 1797-1802.
［24］Wang SL, Lee H, Chen KW, Tsai KJ, Chen CY, Lin P. Cytochrome P4502E1 genetic polymorphisms and lung cancer in a Taiwanese population［J］. Lung Cancer, 1999, 26(1): 27-34.
［25］Wong NA, Rae F, Simpson KJ, Murray GD, Harrison DJ. Genetic polymorphisms of cytochrome p4502E1 and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a white population: a study and literature review, including meta-analysis［J］. Mol Pathol, 2000, 53(2): 88-93.
［26］Lucas D, Menez C, Floch F, Gourlaouen Y, Sparfel O, Joannet I, et al. Cytochromes P4502E1 and P4501A1 genotypes and susceptibility to cirrhosis or upper aerodigestive tract cancer in alcoholic caucasians［J］. Alcohol Clin Exp Res, 1996, 20(6): 1033-1037.
［27］Marques CF, Koifman S, Koifman RJ, Boffetta P, Brennan P, Hatagima A. Influence of CYP1A1, CYP2E1, GSTM3 and NAT2 genetic polymorphisms in oral cancer susceptibility: results from a case-control study in Rio de Janeiro［J］. Oral Oncol, 2006, 42(6): 632-637.
［28］Ruwali M, Khan AJ, Shah PP, Singh AP, Pant MC, Parmar D. Cytochrome P450 2E1 and head and neck cancer: interaction with genetic and environmental risk factors［J］. Environ Mol Mutagen, 2009, 50(6): 473-482.
