Genetic Polymorphism of CYP2A6 and Its Relationship with Nicotine Metabolism in Male Bataknese Smokers Suffered from Lung Cancer in Indonesia

Noni Novisari Soeroso; Rozaimah Zain-Hamid; Bintang Sinaga; Ahmad Sadewa; Tamsil Syafiuddin; Elisna Syahruddin; Gino Tann; Erna Mutiara

doi:10.3889/oamjms.2018.259

Authors

Noni Novisari Soeroso Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155
Rozaimah Zain-Hamid Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155
Bintang Sinaga Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155
Ahmad Sadewa Department of Biochemistry, Faculty of Medicine, Gadjah Mada University, Jl. Farmako Sekip Utara, Yogyakarta 55281
Tamsil Syafiuddin Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155
Elisna Syahruddin Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Indonesia, Jl. Persahabatan Raya No.1, Jakarta 13230
Gino Tann Department of Clinical Pathology, Faculty of Medicine, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155
Erna Mutiara Department of Biostatistics, Faculty of Public Health, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155

DOI:

https://doi.org/10.3889/oamjms.2018.259

Keywords:

Polymorphism of CYP2A6 gene, Bataknese, Lung Cancer, Nicotine metabolism, Smokers

Abstract

BACKGROUND: Cytochrome P450 2A6 (CYP2A6) is known as an enzyme which is responsible for the metabolism of chemical compounds.

AIM: This study aimed to analyse the relationship between CYP2A6 gene polymorphism with nicotine metabolism rates and lung cancer incidence among smokers of Batak ethnic group in Indonesia.

METHODS: This study was a case-control study involving 140 research subjects through a purposive sampling technique from three hospitals in Medan, Indonesia. An examination of nicotine metabolism rates was conducted for all subjects using the 3HC/cotinine ratio parameter with LC-MS/MS technique. The examination of the CYP2A6 gene was performed with PCR-RFLP. Data were analysed with Conditional Logistic Regression test using Epi Info 7.0 software.

RESULTS: The allele frequencies of CYP2A6*1A, CYP2A6*1B, and CYP2A6*4A found were 44.3%, 48.9%, and 6.8%, respectively. The *1B allele showed the highest metabolism rate. It is found that slow metabolizer individuals were 5.49 times more likely to develop lung cancer (P = 0.01, 95%CI 1.2-24.8).

CONCLUSION: Among the Bataknese smokers studied, the CYP2A6*1B allele was found to be the most common allele and showed the highest rate of nicotine metabolism. However, the results show the insignificant relationship among CYP2A6 genetic polymorphism, nicotine metabolism, and lung cancer incidence.

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References

Parkin DM, Bray F, Ferlay J & Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2000; 94(2):153-156. https://doi.org/10.1002/ijc.1440 PMid:11668491

GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer, 2012.

Medical Research Council. Tobacco smoking and cancer of the lung. Br Med J. 1957; 1(5034):1523-1524. https://doi.org/10.1136/bmj.1.5034.1523

Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics. 1996; 6:1-42. https://doi.org/10.1097/00008571-199602000-00002 PMid:8845856

Ding S, Lake BG, Friedberg T, Wolf CR. Expression and alternative splicing of the cytochrome P450 CYP2A7. Biochem J. 1995; 306:161-166. https://doi.org/10.1042/bj3060161 PMid:7864805 PMCid:PMC1136496

Nakajima M, Yamamoto T, Nunoya K, Yokoi T, Nagashima K, Inoue, K, et al. 'Role of human cytochrome P4502A6 in C-oxidation of nicotine'. Drug Metab Dispos. 1996; 24(1):1212-1217. PMid:8937855

Yamazaki H, Inoue K, Hashimoto M, Shimada T. Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Archtoxicol. 1999; 73:65â€“70. https://doi.org/10.1007/s002040050588

Zhang XL, Su T, Zhang QY, Gu J, Caggana M, Li HM, et al. Genetic polymorphism of the human CYP2A13 gene: identification of single-nucleotide polymorphisms and functional characterization of an Arg257Cys variant. J Pharmacol Exp Ther. 2002; 302:416â€“423. https://doi.org/10.1124/jpet.302.2.416 PMid:12130698

Cheng XY, Chen GL, Zhang WX, Zhou G, Wang D & Zhou HH. Arg257Cys polymorphism of CYP2A13 in a Chinese population. Clin Chim Acta. 2004; 343:213â€“216. https://doi.org/10.1016/j.cccn.2004.01.017 PMid:15115698

Yoshida R, Nakajima M, Watanabe Y, Kwon JT & Yokoi T. Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism. Br J Clin Pharmacol. 2002; 54(5):511-517. https://doi.org/10.1046/j.1365-2125.2002.01667.x PMid:12445030 PMCid:PMC1874463

Su T, Bao Z, Zhang QT, Smith TJ, Hong JY & Ding X. Human cytochrome p450 CYP2A13 : predominant expression in the respiratory tracts and its high efficiency metabolic activation of a tobacco specific carcinogen, 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-butanone. Cancer Res. 2000; 60(18):5074-5079. PMid:11016631

Nakajima M, Yamamoto T, Kuroiwa Y & Yokoi T. Improved highly sensitive method for determination of nicotine and cotinine in human plasma by high-performance liquid chromatography. J Chromatogr Biomed Sci Appl. 2000; 742(1):211-215. https://doi.org/10.1016/S0378-4347(00)00149-3

Nakajima M, Kwon J-T, Tanaka N, Zenta T, Yamamoto Y, Yamamoto H, et al. Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans. Clin Pharmacol Ther. 2001; 69:72-78. https://doi.org/10.1067/mcp.2001.112688 PMid:11180041

Caraballo RS, Giovino GA, Pechacek TF, Mowery MS, Richter PA, Strauss WJ, et al. Racial and ethnic differences in serum cotinine levels of cigarette smokers. JAMA. 1998; 280:135-139. https://doi.org/10.1001/jama.280.2.135 PMid:9669785

PeÃ‚rez-Stable EJ, Herrera B, Jacob P III, Benowitz NL. Nicotine metabolism and intake in black and white smokers. JAMA. 1998; 280:152-156. https://doi.org/10.1001/jama.280.2.152

Fujieda M, Yamazaki H, Saito T, Kiyotani K, Gyamfi MA, Sakurai M, et al. Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behaviour and tobacco related lung cancer risk in male japanese smokers. Carcinogenesis. 2004; 25(12):2451-2458. https://doi.org/10.1093/carcin/bgh258 PMid:15308589

Tanner J-A, Henderson JA, Buchwald D, Howard BV, Henderson PN and Tyndale RF. Variation in CYP2A6 and nicotine metabolism among two American Indian tribal groups differing in smoking patterns and risk for tobacco-related cancer. Pharmacogenetics and Genomics. 2017; 27(5):169-178. https://doi.org/10.1097/FPC.0000000000000271 PMid:28181923 PMCid:PMC5382092

Yuan JM, Nelson HH, Carmella SG, Wang R, et al. CYP2A6 genetic polymorphisms and biomarkers of tobacco smoke constituents in relation to risk of lung cancer in the Singapore Chinese Health Study. Carcinogenesis. 2017; 38(4):411-418. https://doi.org/10.1093/carcin/bgx012 PMid:28182203

Swan GE, Benowitz NL, Lessov CN, Jacob P, Tyndale RF & Wilhelmsen K. Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence. Pharmacogenetics and Genomics. 2005; 15:115-125. https://doi.org/10.1097/01213011-200502000-00007 PMid:15861035

Fagan P, Pokhrel P, Herzog TA, Pagano IS, Franke AA, et al. Nicotine metabolism in young adult daily menthol and nonmenthol smokers. Nicotine & Tobacco Research. 2016; 437-446. https://doi.org/10.1093/ntr/ntv109 PMid:25995160 PMCid:PMC4857147

McCracken NW, Cholerton S & Idle JR. Cotinine formation by cDNA-expressed human cytochromes P450. Medical Science Research. 1992; 20:877-878.

Oscarson M, McLellan RA, GullstÃ©n H, AgÃºndez JAG, BenÃtez J, Rautio A, Raunio H, et al. Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. FEBS Letters. 1999; 460:321-327. https://doi.org/10.1016/S0014-5793(99)01364-2

Pribadi I. Kebudayaan Batak, Mata Kuliah Budaya Nusantara, Sekolah Tinggi Akutansi Negara Spesialisasi Penilai/PBB Jakarta, 2009.

Benowitz NL. Cotinine is a biomarker of environmental tobacco smoke exposure. Epidemiol Rev. 1996; 18(2):188-204. https://doi.org/10.1093/oxfordjournals.epirev.a017925 PMid:9021312

Nakajima M, Yoshida R, Fukami T, McLeod HL & Yokoi T. Novel human CYP2A6 alleles confound gene deletion analysis. FEBS Lett. 2004; 569(1-3):75-81. https://doi.org/10.1016/j.febslet.2004.05.053 PMid:15225612

Rubinstein ML, Benowitz NL, Auerback GM and Moscicki AB. Rate of nicotine metabolism and withdrawal symptoms in adolescent light smokers. Pediatrics. 2008; 122(3):e643-e647. https://doi.org/10.1542/peds.2007-3679 PMid:18762498 PMCid:PMC2722964

Mong C, Goron EB & Fuller C.High prevalence of lung cancer in surgical cohort of lung cancer patients a decade after smoking cessation. J Cardiothorac Surg. 2011; 6(19):1-7. https://doi.org/10.1186/1749-8090-6-19

Afrose R, Akram M, Masroor K, Siddiqui SA. Correlation of age and gender with different histological subtypes of primary lung cancer. Med. J Dr. D.Y, Patil University. 2015; 8(4):447-451. https://doi.org/10.4103/0975-2870.160783

Siregar AP. Determinan Perilaku Merokok Siswa Sekolah Dasar di Desa Simatahari Kecamatan Kota Pinang Kabupaten Labuhan Batu Selatan. Program Studi Magister Ilmu Kesehatan Masyarakat. Fakultas Kesehatan Masyarakat USU, 2015.

Malik PS, Sharma MC, Mohanti BK, Shukla NK, Deo SVS, Mohan A, et al. Clinico-pathological Profile of Lung Cancer at AIIMS: A Changing Paradigm in India. Asian Pacific J Cancer Prev. 2013; 14(1):489-494. https://doi.org/10.7314/APJCP.2013.14.1.489

Brooks DR, Austin JH, Heelan RT, Ginsberg MS, Shin V, Olson SH, et al. Influence of type of cigarette on peripheral versus central lung cancer. Cancer Epidemiol Biomarkers Prev. 2005; 14:576-581. https://doi.org/10.1158/1055-9965.EPI-04-0468 PMid:15767332

Thun ML, Lally CA, Flannery JL, Calle EE, Flanders WD, Heath CW. Cigarrete smoking and changes in the histopathology of lung cancer. J Natl Cancer Inst. 1997; 89(1):1580â€“1586. https://doi.org/10.1093/jnci/89.21.1580 PMid:9362155

Stellman SD, Muscat JE, Thompson S, Hoffmann D, Wynder EL. Risk of squamous cell carcinoma and adenocarcinoma of the lung in relation to lifetime alter cigarette smoking. Cancer. 1997; 80:382-388. https://doi.org/10.1002/(SICI)1097-0142(19970801)80:3<382::AID-CNCR5>3.0.CO;2-U

Devesa SS, Bray F, Vizcaino AP, Parkin DM. International lung cancer trends by histologic type: male: female differences diminishing and adenocarcinoma rates rising. Int J Cancer. 2005; 117:294-299. https://doi.org/10.1002/ijc.21183 PMid:15900604

Nakada T, Kiyotani K, Iwano S, Uno T, Yokohira M, et al. Lung tumorigenesis promoted by anti-apoptotic effects of cotinine, a nicotinae metabolite through activation of PI3K/Akt pathway. J Toxicol Sci. 2012; 37:555â€“563. https://doi.org/10.2131/jts.37.555 PMid:22687995

Tyndale RF, Sellers EM. Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior. Therapeutic Drug Monitoring. 2002; 24:163â€“171. https://doi.org/10.1097/00007691-200202000-00026