Christine Patramurti, Sugiyanto ., Arief Nurrochmad, Sudibyo Martono


Cytochrome P450 2A6 (CYP2A6) is the principal enzyme involved in the metabolic activation of tobacco-specific nitrosamines to their ultimate carcinogenic forms and metabolism of nicotine. The present study was developed to investigate the genetic polymorphism of CYP2A6 in Javanese Indonesian subjects carrying the CYP2A6*1 allele and the CYP2A6*4. The whole gene deletion of CYP2A6 (CYP2A6*4) may inhibit smokers from giving up smoking, but appears to function as a protective factor against to some cancer. However, the investigation of these allele, a major functional polymorphisms common in Asian populations, have not been reported among Javanese Indonesian population. A single polymerase chain reaction-restriction fragment length polymorphism was used to resolve the genotypes into CYP2A6*1 (wild type) and CYP2A6*4 (CYP2A6del). The sample studied consisted of 100 healthy subject that consist of 50 non smokers and 50 smoker from Javanese Indonesian population. The allele frequencies of *1 (wild type) and *4, were 47.5 and 52.5%, respectively. When the two allel were considered simultaneously, among the non-smokers, 45% were genotyped for CYP2A6*1/*4 and 5% were genotyped for CYP2A6*4/*4; on the other hand all of the smoker were genotyped for CYP2A6*1/*4 and there was no homozygote of wild type. Based on the data collected, it could be concluded that the polymorphism of CYP2A6 were detected in among Javanese population sample study and the allele frequencies of CYP2A6*4 were high.

Key word: Polymorphism, CYP2A6*1, CYP2A6*4, Javanese Indonesian

Full Text:

PDF (PP.11-19)


Ando M., Hamajima N., Ariyoshi N., Kamataki T., Matsuo K., Ohno Y., 2003. Association of CYP2A6 gene deletion with cigarette smoking status in Japanese adults. J. Epidemiol. 13, 176–181.

Ariyoshi N., Miyamoto M., Umetsu Y., Kunitoh H., Dosaka-Akita H., Sawamura YI., Yokota J., Nemoto N., Sato K., and Kamataki T., 2002. Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers. Cancer Epidemiol. Biomark. Prev. 11, 890–894.

Ariyoshi N., Takahashi Y., Miyamoto M., Umetsu Y., Daigo S., et al., 2000. Structural characterization of a new variant of the CYP2A6 gene (CYP2A6*1B) apparently diagnosed as heterozygotes of CYP2A6*1A and CYP2A6*4C. Pharmacogenetics. 10, 687–693.

Benowitz NL., Dains KM., Dempsey D., Wilson M., Jacob P., 2011. Racial differences in the relationship between number of cigarettes smoked and nicotine and carcinogen exposure. Nic. Tob. Res. 13, 772–783.

B-Rao C., 2001. Sample size considerations in genetic polymorphism studies. Human Heredity, 52, 191–200.

Daigo S., Takahashi Y., Fujieda M., Ariyoshi N., Yamazaki H., et al., 2002. A novel mutant allele of the CYP2A6 gene (CYP2A6*11 ) found in a cancer patient who showed poor metabolic phenotype towards tegafur. Pharmacogenetics. 12, 299–306.

Fernandez-Salguero P., Hoffman SM., Cholerton S., Mohrenweiser H., et al., 1995. A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Am. J. Hum. Genet. 57, 651–660.

Fujieda M., Yamazaki H., Saito T., Kiyotani K., Gyamfi MA., et al., 2004. Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis. 25, 2451–2458.

Gambier N., Batt AM., Marie B., Pfister M., Siest G., Visvikis-Siest S., 2005. Association of CYP2A6*1B genetic variant with the amount of smoking in French adults from the Stanislas cohort. Pharmacogenomics J. 5, 271–275.

Gullstén H., 2000. Significance of Polymorphism in CYP2A6 Gene. Academic Dissertation. Department of Pharmacology and Toxicology Universtiy of Oulu, Oulu.

Heravi RE., Ramezani M., Behravan J., 2010. Association Between Nicotine Metabolism and CYP2A6*1 and CYP2A6*4 Genotypes in an Iranian Population. DNA Cell Biol. 29, 369–373.

Hukkanen J., Jacob PIII., Benowitz NL., 2005. Metabolism and disposition kinetics of nicotine. Pharmacol. Rev. 57, 79–115.

Islam MS., Ahmed MU., Sayeed, MSB., Maruf AA., Mostofa AGM., Hussain SMA., Kabir Y., Daly AK., Hasnat A., 2013. Lung cancer risk in relation to nicotinic acetylcholine receptor, CYP2A6 and CYP1A1 genotypes in the Bangladeshi population. Clin. Chim. Acta Int. J. Clin. Chem. 416, 11–19.

Johnstone E., Benowitz N., Cargill A., Jacob R., Hinks L., Day I., Murphy M., Walton R., 2006. Determinants of the rate of nicotine metabolism and effects on smoking behavior. Clin. Pharmacol. Ther. 80, 319–330.

Kamataki T., Fujita K., Nakayama K., Yamazaki Y., Miyamoto M., Ariyoshi N., 2002. Role of human cytochrome P450 (CYP) in the metabolic activation of nitrosamine derivatives: application of genetically engineered Salmonella expressing human CYP. Drug Metab. Rev. 34, 667–676.

Kubota T., Nakajima-Taniguchi C., Fukuda T., Funamoto, M., Maeda M., Tange E., Ueki R., Kawashima K., Hara H., Fujio Y., Azuma J., 2006. CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation. Pharmacogenomics J. 6, 115–119.

Kushida H., Fujita K., Suzuki A., Yamada M., Endo T., Nohmi T., Kamataki T., 2000. Metabolic activation of N-alkylnitrosamines in genetically engineered Salmonella typhimurium expressing CYP2E1 or CYP2A6 together with human NADPH-cytochrome P450 reductase. Carcinogenesis. 21, 1227–1232.

Kwon JT., Nakajima, M., Chai S., Yom YK., Kim HK., Yamazaki H., Sohn DR., Yamamoto T., Kuroiwa Y., Yokoi T., 2001. Nicotine metabolism and CYP2A6 allele frequencies in Koreans. Pharmacogenetics. 11, 317–323.

Lea R., Benowitz N., Green M., Fowles J., Vishvanath A., Dickson S., Lea M., Woodward A., Chambers G., Phillips, D., 2005. Ethnic differences in nicotine metabolic rate among New Zealanders. N. Z. Med. J. 118, U1773.

Liu T., David SP., Tyndale RF., Wang H., Zhou Q., Ding P., He YH., Yu XQ., Chen W., Crump C., Wen XZ., Chen WQ., 2011. Associations of CYP2A6 genotype with smoking behaviors in southern China. Addict. Abingdon Engl. 106, 985–994.

Liu T., Xie CB., Ma WJ., Chen WQ., 2013. Association between CYP2A6 genetic polymorphisms and lung cancer: a meta-analysis of case-control studies. Environ. Mol. Mutagen. 54, 133–140.

Messina ES., Tyndale RF., Sellers EM., 1997. A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J. Pharmacol. Exp. Ther. 282, 1608–1614.

Minematsu N., Nakamura H., Furuuchi M., Nakajima, T., Takahashi S., Tateno H., Ishizaka A., 2006. Limitation of cigarette consumption by CYP2A6*4, *7 and *9 polymorphisms. Eur. Respir. J. 27, 289–292.

Minematsu N., Nakamura H., Iwata M., Tateno H., Nakajima T., Takahashi S., Fujishima S., Yamaguchi K., 2003. Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema. Thorax. 58, 623–628.

Muroi A., Kiyotani K., Fujieda M., Ishikawa H., Takeshi T., Iwano S., Yamazaki H., Kamataki T., 2012. Effect of Genetic Polymorphism of CYP2A6 on Individual Susceptibility to Colorectal Tumors in Japanese Smokers. J. Cancer Ther. 3, 207–215.

Mwenifumbo JC., Al Koudsi N., Ho MK., Zhou Q., Hoffmann EB., Sellers EM., Tyndale RF., 2008. Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of Black African descent. Hum. Mutat. 29, 679–688.

Nagano T., Shimizu M., Kiyotani K., Kamataki T., Takano R., Murayama N., Shono F., Yamazaki H., 2010. Biomonitoring of urinary cotinine concentrations associated with plasma levels of nicotine metabolites after daily cigarette smoking in a male Japanese population. Int. J. Environ. Res. Public. Health. 7, 2953–2964.

Nakajima, M., Fukami, T., Yamanaka, H., Higashi, E., Sakai, H., Yoshida, R., Kwon, J.-T., McLeod, H.L., and Yokoi, T., 2006. Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations. Clin. Pharmacol. Ther. 80, 282–297.

Nakajima M., Kwon JT., Tanaka N., Zenta T., Yamamoto Y., Yamamoto H., Yamazaki H., Yamamoto T., Kuroiwa Y., Yokoi T., 2001. Relationship between interindi-vidual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans. Clin. Pharmacol. Ther. 69, 72–78.

Nakajima M., Yokoi, T., 2005. Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. Drug Metab. Pharmacokinet. 20, 227–235.

Nowell S., Sweeney C., Hammons G., Kadlubar FF., Lang NP., 2002. CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk. Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol. 11, 377–383.

Nunoya KI., Yokoi T., Kimura K., Kainuma T., Satoh K., Kinoshita M., Kamataki T., 1999. A new CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride in humans. J. Pharmacol. Exp. Ther. 289, 437–442.

Oscarson M., 2001. Genetic polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene: implications for interindividual differences in nicotine metabolism. Drug Metab. Dispos. Biol. Fate Chem. 29, 91–95.

Oscarson M., Gullstén H., Rautio A., Bernal ML., Sinues B., Dahl ML., Stengård JH., Pelkonen O., Raunio H., Ingelman-Sundberg M., 1998. Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase. FEBS Lett. 438, 201–205.

Oscarson M., McLellan RA., Gullstén H., Yue QY., Lang MA., Bernal ML., Sinues B., Hirvonen A., Raunio H., Pelkonen O., Ingelman-Sundberg M., 1999. Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Lett. 448, 105–110.

Pelkonen, O., Raunio, H., Rautio, A., and Lang, M., 1999. Xenobiotic-metabolizing enzymes and cancer risk: correspondence between genotype and phenotype. IARC Sci. Publ. 77–88.

Rao Y., Hoffmann E., Zia M., Bodin L., Zeman M., Sellers EM., Tyndale RF., 2000. Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. Mol. Pharmacol. 58, 747–755.

Raunio HC., Hakkola J., Pelkonen O., 2008. The CYP2A Subfamily, in: Cytochromes P450: Role in the Metabolism and Toxicity of Drugs and Other Xenobiotics. Royal Society of Chemistry.

Raunio H., Rautio A., Gullstén H., Pelkonen O., 2001. Polymorphisms of CYP2A6 and its practical consequences. Br. J. Clin. Pharmacol. 52, 357–363.

Rautio A., 2003. Polymorphic CYP2A6 and its clinical and toxicological significance. Pharmacogenomics J. 3, 5–7.

Schoedel KA., Hoffmann EB., Rao Y., Sellers, EM., Tyndale RF., 2004. Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics. 14, 615–626.

Tan W., Chen GF., Xing DY., Song CY., Kadlubar FF., Lin DX., 2001. Frequency of CYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population. Int. J. Cancer. 95, 96–101.

Topcu Z., Chiba I., Fujieda M., Shibata T., Ariyoshi N., Yamazaki H., Sevgican F., Muthumala M., Kobayashi H., Kamataki T., 2002. CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka. Carcinogenesis. 23, 595–598.

Wang L., Zang W., Liu J., Xie D., Ji W., Pan Y., Li Z., Shen J., Shi, Y., 2013. Association of CYP2A6*4 with susceptibility of lung cancer: a meta-analysis. PloS One. 8, e59556.

Yang M., Kunugita N., Kitagawa K., Kang SH., Coles B., Kadlubar FF., Katoh T., Matsuno K., Kawamoto T., 2001. Individual differences in urinary cotinine levels in Japanese smokers: relation to genetic polymorphism of drug-metabolizing enzymes. Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol. 10, 589–593.

Yoshida R., Nakajima M., Watanabe Y., Kwon JT., Yokoi T., 2002. Genetic poly-morphisms in human CYP2A6 gene causing impaired nicotine metabolism. Br. J. Clin. Pharmacol. 54, 511–517.

Yusof W., Gan, SH., 2009. High prevalence of CYP2A6*4 and CYP2A6*9 alleles detected among a Malaysian population. Clin. Chim. Acta Int. J. 403, 105–109.

DOI: http://dx.doi.org/10.14499/indonesianjpharm26iss1pp11


  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

Indonesian J Pharm indexed by:

analytics View My Stats