Vol 6, No 2 (2019) > Articles >

Genetic Polymorphism Cytochrome P450 2A6 Allele *4 and *9: Studi on Glycohemoglobine Level Among Javanese Indonesian Smokers

Christine Patramurti , Fenty Fenty



Nicotine, the active compound in cigarettes, was considered as the risk factor for type 2 diabetes mellitus (T2DM). In the human body, nicotine would be metabolized by the enzyme cytochrome P450 2A6 (CYP2A6). CYP2A6 was known to be highly polymorphic. The active form of this gene was CYP2A6 *1, while the CYP2A6 *4 and CYP2A *9 alleles were the inactive alleles. The presence of this inactive allele caused the decreased activity of CYP2A6 so that it would affect the level of nicotine in the blood and would eventually cause an increased blood sugar levels. This study aimed to determine the effect of CYP2A6 polymorphism on glycohemoglobine levels among Javanese smokers. The blood sugar levels were measured by hemoglobin A1c (HbA1c). In this study, 33 active smokers involved in the study were identified as slow metabolizers, by which 63.9% of all test participants had CYP2A6 *1/*4 genotype and as many as 6.1% of the test participants had the CYP2A6 *1/*4/*9. The HbA1c levels among the participants have been analyzed, 28 participants were in normal range (4.83-5.56%); 4 participants were identified in prediabetes condition (5.70% - 5.97%) and 1 participant was in diabetes with HbA1c level was 7.16%. This condition indicates that the presence of CYP2A6 *4 and *9 alleles will affect HbA1c levels which can eventually lead to T2DM disease.

Keywords: polymorphism; CYP2A6*4; CYP2A6 *9; glycohemoglobine

Published at: Vol 6, No 2 (2019) pages: 82-88

DOI: 10.7454/psr.v6i2.4488

Access Counter: 2127 views

Full PDF Download


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. Journal of Epidemiology /Japan Epidemiological Association, 13(3), 176-181

Anttila, S., Raunio, H., & Hakkola, J. (2011). Cytochrome P450-Mediated Pulmonary Metabolism of Carcinogens. American Journal of Respiratory Cell and Molecular Biology, 44(5), 583-590

American Diabetes Association. (2010). Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 33

American Diabetes Association. (2011). Executive Summary: Standards of Medical Care in Diabetes-2011. Diabetes Care, 34(Supplement 1), S4-S10

Bajaj, M. (2012). Nicotine and Insulin Resistance: When the Smoke Clears. Diabetes, 61(12), 3078-3080

Bergman, B. C., Perreault, L., Hunerdosse, D., Kerege, A., Playdon, M., Samek, A. M., & Eckel, R. H. (2012). Novel and Reversible Mechanisms of Smoking-Induced Insulin Resistance in Humans. Diabetes, 61(12), 3156-3166

Bergman, B. C., Perreault, L., Hunerdosse, D. M., Koehler, M. C., Samek, A. M., & Eckel, R. H. (2009). Intramuscular lipid metabolism in the insulin resistance of smoking. Diabetes, 58(10), 2220-2227

Boffetta, P. (2008). Tobacco smoking and risk of bladder cancer. Scandinavian Journal of Urology and Nephrology. Supplementum, (218), 45-54

Borowitz, J. L., & Isom, G. E. (2008). Nicotine and Type 2 Diabetes. Toxicological Sciences, 103(2), 225-227

Brown, P. J., Bedard, L. L., Reid, K. R., Petsikas, D., & Massey, T. E. (2007). Analysis of CYP2A contributions to metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human peripheral lung microsomes. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 35(11), 2086-2094

Buell, C., Kermah, D., & Davidson, M. B. (2007). Utility of A1C for diabetes screening in the 1999 2004 NHANES population. Diabetes Care, 30(9), 2233-2235

Fujieda, M., Yamazaki, H., Saito, T., Kiyotani, K., Gyamfi, M. A., Sakurai, M., … Kamataki, T. (2004). Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis, 25(12), 2451-2458

Hecht, S. S. (2003). Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nature Reviews. Cancer, 3(10), 733-744

Hecht, S. S. (2012). Lung carcinogenesis by tobacco smoke. International Journal of Cancer. Journal International Du Cancer, 131(12), 2724-2732

Houston, T. K., Person, S. D., Pletcher, M. J., Liu, K., Iribarren, C., & Kiefe, C. I. (2006). Active and passive smoking and development of glucose intolerance among young adults in a prospective cohort: CARDIA study. BMJ, 332(7549), 1064-1069

Hukkanen, J., Jacob, P., & Benowitz, N. L. (2005). Metabolism and disposition kinetics of nicotine. Pharmacological Reviews, 57(1), 79-115

International Diabetes Federation (2017). IDF Diabetes Atlas Eighth edition 2017. IDF

Jyothirmayi, B., Kaviarasi, S., & William, E. (2013). Study of glycated hemoglobin in chronic cigarette smokers. International Journal of Pharmaceutical and Clinical Research, 5(1), 4-6

Liu, T., Chen, W.-Q., David, S. P., Tyndale, R. F., Wang, H., Chen, Y.-M., … Ling, W.-H. (2011). Interaction between heavy smoking and CYP2A6 genotypes on type 2 diabetes and its possible pathways. European Journal of Endocrinology/European Federation of Endocrine Societies, 165(6), 961-967

Liu, T., David, S. P., Tyndale, R. F., Wang, H., Zhou, Q., Ding, P., … Chen, W.-Q. (2011). Associations of CYP2A6 genotype with smoking behaviors in southern China. Addiction (Abingdon, England), 106(5), 985-994

Mallery, S. R., Tong, M., Michaels, G. C., Kiyani, A. R., & Hecht, S. S. (2014). Clinical and Biochemical Studies Support Smokeless Tobacco’s Carcinogenic Potential in the Human Oral Cavity. Cancer Prevention Research, 7(1), 23-32

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. The European Respiratory Journal, 27(2), 289-292

Mwenifumbo, J. C., Al Koudsi, N., Ho, M. K., Zhou, Q., Hoffmann, E. B., Sellers, E. M., & Tyndale, R. F. (2008). Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of Black African descent. Human Mutation, 29(5), 679-688

Mwenifumbo, J. C., Sellers, E. M., & Tyndale, R. F. (2007). Nicotine metabolism and CYP2A6 activity in a population of black African descent: Impact of gender and light smoking. Drug and Alcohol Dependence, 89(1), 24-33

Nakajima, M., Yoshida, R., Fukami, T., McLeod, H. L., & Yokoi, T. (2004). Novel human CYP2A6 alleles confound gene deletion analysis. FEBS Letters, 569(1-3), 75-81

Nilsson, P. M., Gudbjörnsdottir, S., Eliasson, B., & Cederholm, J. (2004). Smoking is associated with increased HbA1c values and microalbuminuria in patients with diabetes-data from the National Diabetes Register in Sweden. Diabetes & Metabolism, 30(3), 261-268

Patramurti, C. (2017). Studi Genotipe Sitokrom P450 2A6 Alel CYP2A6 *4 dan CYP2A6 *9 pada Subyek Uji Perokok Suku Jawa Indonesia (Genotyping Study of Cytochrome P450 2A6 Alel CYP2A6 *1 and CYP2A6 *9 among Javanese Indonesian Smokers), 15(1), 50-56

Patramurti, C., Nurrochmad, A., Martono, S., Science, P., Mada, G., & Chemistry, P. (2015). Poymorphism of Cytochrome P450 2A6 (CYP2A6 *1 AND CYP2A6 *4) among Javaneses Indonesia Smoker and Non Smoker, 26(1), 11-19

Pitarque, M., Richter, O., Oke, B., Berkkan, H., Oscarson, M., and Ingelman- Sundberg, M. (2001). Identification of a Single Nucleotide Polymorphism in the TATA Box of the CYP2A6 Gene: Impairment of Its Promoter Activity, Biochemical and Biophysical Research Communications, 284, 455-460

Rao, Y., Hoffmann, E., Zia, M., Bodin, L., Zeman, M., Sellers, E. M., & Tyndale, R. F. (2000). Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. Molecular Pharmacology, 58(4), 747-755

Raunio, H., & Rahnasto-Rilla, M. (2012). CYP2A6: genetics, structure, regulation, and function. Drug Metabolism and Drug Interactions, 27(2), 73-88

Schoedel, K. a, Hoffmann, E. B., Rao, Y., Sellers, E. M., & Tyndale, R. F. (2004). Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics, 14(9), 615-626

Shields, P. G. (2002). Molecular epidemiology of smoking and lung cancer. Oncogene, 21(45), 6870-6876

Soelistijo, S.A; Novida, H.; Rudijanto, A.; Soewondo, P.; Suastika, K.; Manaf, A. et al. (2015). Konsensus Pengendalian dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia 2015. Perkeni

The International Expert Committee. (2009). International Expert Committee Report on the Role of the A1C Assay in the Diagnosis. Diabetes Care, 32(7)

Vlassopoulos, A., Lean, M. E., & Combet, E. (2013). Influence of smoking and diet on glycated haemoglobin and ‘pre-diabetes’ categorisation: a cross-sectional analysis. BMC Public Health, 13, 1013

Wang, J., Xu, Y., Li, J., Sun, X., Wang, L.-P., & Ji, W.-Y. (2012). The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation in laryngeal carcinoma. Oral Oncology, 48(6), 541-546

Willi, C., Bodenmann, P., Ghali, W. A., Faris, P. D., & Cornuz, J. (2007). Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. JAMA, 298(22), 2654-2664

Xie, X., Liu, Q., Wu, J., & Wakui, M. (2009). Impact of cigarette smoking in type 2 diabetes development. Acta Pharmacologica Sinica, 30(6), 784-787

Xu, T., Guo, L., Wang, P., Song, J., Le, Y., Viollet, B., & Miao, C. (2012). Chronic Exposure to Nicotine Enhances Insulin Sensitivity through a 7 Nicotinic Acetylcholine Receptor-STAT3 Pathway, 7(12), 1-10

Yusof, W., & Gan, S. H. (2009). High prevalence of CYP2A6*4 and CYP2A6*9 alleles detected among a Malaysian population. Clinica Chimica Acta; International Journal of Clinical Chemistry, 403(1–2), 105-109.