Skip to main content

Advertisement

SpringerLink
Log in

Variation in N-acetyltransferase 2 (NAT2), smoking and risk of prostate cancer in the Slovak population

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

N-acetyltransferase 2 (NAT2) is an enzyme involved in the biotransformation of xenobiotics, mainly aromatic and heterocyclic amines and hydrazines, all of which represent an important class of carcinogens found in tobacco smoke. Polymorphism in NAT2 gene is reported to be associated with susceptibility to various types of cancer. This study investigated the relationship between the NAT2 polymorphism and the risk of prostate cancer with reference to the link between cigarette smoking and the xenobiotic-metabolizing enzyme NAT2. Overall, 281 cases and 395 controls from Slovakia were studied using polymerase chain reaction–restriction fragment length polymorphism assay. We found no statistically significant association between NAT2 genotypes and prostate cancer risk (slow acetylation vs. rapid acetylation: OR 1.13; 95 % CI 0.83–1.55). We report here a statistically significant correlation between the NAT2*5C/NAT2*6A slow acetylator genotype and the risk for developing prostate cancer (OR 2.91; 95 % CI 1.43–5.94; p = 0.003) when compared with the rapid phenotype. Smokers with NAT2 rapid phenotype had a five percent (5 %) reduced risk of prostate cancer compared with non-smokers carrying the rapid acetylator genotype. The association was reversed among smokers and non-smokers with NAT2 slow phenotype. On the basis of the foregoing, we conclude that the NAT2 phenotypes whether alone or in association with smoking do not correlate with susceptibility to prostate cancer within the Slovak population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jang TL, Yossepowitch O, Bianco FJ Jr, Scardino PT. Low risk prostate cancer in men under age 65: the case for definitive treatment. Urol Oncol. 2007;25:510–4.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Ondrusova M, Ondrus D, Karabinos J, Muzik J, Kliment J, Gulis G. Trends in prostate cancer incidence and mortality before and after the introduction of PSA testing in the Slovak and Czech Republics. Tumori. 2011;97(2):149–55.

    PubMed  Google Scholar 

  3. Sivoňová MK, Dobrota D, Dušenka R, Waczulíková I, Slezák P, Matáková T, Mahmoodová S, Mištuna D, Kliment J. Effect of CYP17 and PSA gene polymorphisms on prostate cancer risk and circulating PSA levels in the Slovak population. Mol Biol Rep. 2012;39(8):7871–80.

    Article  PubMed  Google Scholar 

  4. Stamatiou KN. Elderly and prostate cancer screening. Urol J. 2011;8(2):83–7.

    PubMed  Google Scholar 

  5. Sivonova MK, Dobrota D, Matakova T, Dusenka R, Grobarcikova S, Habala V, Salagovic J, Tajtakova M, Pidanicova A, Valansky L, Lachvacs L, Kliment J Jr, Nagy V, Kliment J. Microsomal epoxide hydrolase polymorphisms, cigarette smoking and prostate cancer risk in the Slovak population. Neoplasma. 2012;59(1):79–84.

    Article  CAS  PubMed  Google Scholar 

  6. Clavel J. Progress in the epidemiological understanding of gene–environment interactions in major diseases: cancer. C R Biol. 2007;330(4):306–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Hein DW. N-acetyltransferase SNPs: emerging concepts serve as a paradigm for understanding complexities of personalized medicine. Expert Opin Drug Metab Toxicol. 2009;5(4):353–66.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Liu L, Von Vett A, Zhang N, Walters KJ, Wagner CR, Hanna PE. Arylamine N-acetyltransferases: characterization of the substrate specificities and molecular interactions of environmental arylamines with human NAT1 and NAT2. Chem Res Toxicol. 2007;20(9):1300–8.

    Article  CAS  PubMed  Google Scholar 

  9. Rajasekaran M, Abirami S, Chen C. Effects of single nucleotide polymorphisms on human N-acetyltransferase 2 structure and dynamics by molecular dynamics simulation. PLoS ONE. 2011;6(9):e25801.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Sim E, Lack N, Wang CJ, Long H, Westwood I, Fullam E, Kawamura A. Arylamine N-acetyltransferases: structural and functional implications of polymorphisms. Toxicology. 2008;254(3):170–83.

    Article  CAS  PubMed  Google Scholar 

  11. Windmill KF, Gaedigk A, Hall PM, Samaratunga H, Grant DM, McManus ME. Localization of N-acetyltransferases NAT1 and NAT2 in human tissues. Toxicol Sci. 2000;54(1):19–29.

    Article  CAS  PubMed  Google Scholar 

  12. Blum M, Grant DM, McBride W, Heim M, Meyer UA. Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol. 1990;9(3):193–203.

    Article  CAS  PubMed  Google Scholar 

  13. Gong C, Hu X, Gao Y, Cao Y, Gao F, Mo Z. A meta-analysis of the NAT1 and NAT2 polymorphisms and prostate cancer: a huge review. Med Oncol. 2011;28(1):365–76.

    Article  CAS  PubMed  Google Scholar 

  14. NAT 2 Nomenclature. http://louisville.edu/medschool/pharmacology/NAT.html.

  15. Walraven JM, Zang Y, Trent JO, Hein DW. Structure/function evaluations of single nucleotide polymorphisms in human N-acetyltransferase 2. Curr Drug Metab. 2008;9(6):471–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Agundez JA. Polymorphisms of human N-acetyltransferases and cancer risk. Curr Drug Metab. 2008;9(6):520–31.

    Article  CAS  PubMed  Google Scholar 

  17. Hein DW, Doll MA, Fretland AJ, Leff MA, Webb SJ, Xiao GH, Devanaboyina US, Nangju NA, Feng Y. Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomark Prev. 2000;9(1):29–42.

    CAS  Google Scholar 

  18. Meyer UA, Zanger UM. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol. 1997;37:269–96.

    Article  CAS  PubMed  Google Scholar 

  19. Hamasaki T, Inatomi H, Katoh T, Aono H, Ikuyama T, Muratani T, Matsumoto T. N-acetyltransferase-2 gene polymorphism as a possible biomarker for prostate cancer in Japanese men. Int J Urol. 2003;10(3):167–73.

    Article  CAS  PubMed  Google Scholar 

  20. de Lima Junior MM, Reis LO, Guilhen AC, Granja F, de Lima Oliveira MN, Ferreira U, Cunha LL, Ward LS. N-acetyltransferase-2 gene polymorphisms and prostate cancer susceptibility in Latin American patients. Med Oncol. 2012;29(4):2889–94.

    Article  PubMed  Google Scholar 

  21. Wadelius M, Autrup JL, Stubbins MJ, Andersson SO, Johansson JE, Wadelius C, Wolf CR, Autrup H, Rane A. Polymorphisms in NAT2, CYP2D6, CYP2C19 and GSTP1 and their association with prostate cancer. Pharmacogenetics. 1999;9(3):333–40.

    Article  CAS  PubMed  Google Scholar 

  22. Hooker S, Bonilla C, Akereyeni F, Ahaghotu C, Kittles RA. NAT2 and NER genetic variants and sporadic prostate cancer susceptibility in African Americans. Prostate Cancer Prostatic Dis. 2008;11(4):349–56.

    Article  CAS  PubMed  Google Scholar 

  23. Iguchi T, Sugita S, Wang CY, Newman NB, Nakatani T, Haas GP. MnSOD genotype and prostate cancer risk as a function of NAT genotype and smoking status. In Vivo. 2009;23(1):7–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Rovito PM Jr, Morse PD, Spinek K, Newman N, Jones RF, Wang CY, Haas GP. Heterocyclic amines and genotype of N-acetyltransferases as risk factors for prostate cancer. Prostate Cancer Prostatic Dis. 2005;8(1):69–74.

    Article  CAS  PubMed  Google Scholar 

  25. Agúndez JA, Martínez C, Olivera M, Gallardo L, Ladero JM, Rosado C, Prados J, Rodriguez-Molina J, Resel L, Benítez J. Expression in human prostate of drug- and carcinogen-metabolizing enzymes: association with prostate cancer risk. Br J Cancer. 1998;78(10):1361–7.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Srivastava DS, Mittal RD. Genetic polymorphism of the N-acetyltransferase 2 gene, and susceptibility to prostate cancer: a pilot study in north Indian population. BMC Urol. 2005;6:5–12.

    Google Scholar 

  27. Costa S, Pinto D, Morais A, Vasconcelos A, Oliveira J, Lopes C, Medeiros R. Acetylation genotype and the genetic susceptibility to prostate cancer in a southern European population. Prostate. 2005;64(3):246–52.

    Article  CAS  PubMed  Google Scholar 

  28. Xue W, Warshawsky D. Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: a review. Toxicol Appl Pharmacol. 2005;206(1):73–93.

    Article  CAS  PubMed  Google Scholar 

  29. Cleary SP, Cotterchio M, Shi E, Gallinger S, Harper P. Cigarette smoking, genetic variants in carcinogen-metabolizing enzymes, and colorectal cancer risk. Am J Epidemiol. 2010;172(9):1000–14.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Klimčáková L, Habalová V, Sivoňová M, Nagy V, Šalagovič J, Židzik J. Effect of NAT2 gene polymorphism on bladder cancer risk in Slovak population. Mol Biol Rep. 2011;38(2):1287–93.

    Article  PubMed  Google Scholar 

  31. Garcia-Martin E. Interethnic and intraethnic variability of NAT2 single nucleotide polymorphisms. Curr Drug Metab. 2008;9:487–97.

    Article  CAS  PubMed  Google Scholar 

  32. Zang Y, Doll MA, Zhao S, States JC, Hein DW. Functional characterization of single-nucleotide polymorphisms and haplotypes of human N-acetyltransferase 2. Carcinogenesis. 2007;28(8):1665–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Touré A, Diop C, Cabral M, Fall M, Lhermitte M, Diouf A, Broly F, Allorge D. Study of NAT2 genetic polymorphism in West African subjects: example of an healthy non-smoker Senegalese population. Mol Biol Rep. 2012;39(12):10489–96.

    Article  PubMed  Google Scholar 

  34. Leff MA, Fretland AJ, Doll MA, Hein DW. Novel human N-acetyltransferase 2 alleles that differ in mechanism for slow acetylator phenotype. J Biol Chem. 1999;274(49):34519–22.

    Article  CAS  PubMed  Google Scholar 

  35. Semiz S, Dujic T, Ostanek B, Velija-Asimi Z, Prnjavorac B, Bego T, Malenica M, Mlinar B, Heljic B, Marc J, Causevic A. Association of NAT2 polymorphisms with type 2 diabetes in a population from Bosnia and Herzegovina. Arch Med Res. 2011;42(4):311–7.

    Article  CAS  PubMed  Google Scholar 

  36. Wang CY, Debiec-Rychter M, Schut HA, Morse P, Jones RF, Archer C, King CM, Haas GP. N-Acetyltransferase expression and DNA binding of N-hydroxyheterocyclic amines in human prostate epithelium. Carcinogenesis. 1999;20(8):1591–5.

    Article  CAS  PubMed  Google Scholar 

  37. Hein DW, Doll MA, Rustan TD, Gray K, Feng Y, Ferguson RJ, Grant DM. Metabolic activation and deactivation of arylamine carcinogens by recombinant human NAT1 and polymorphic NAT2 acetyltransferases. Carcinogenesis. 1993;14(8):1633–8.

    Article  CAS  PubMed  Google Scholar 

  38. Reistad R, Nyholm SH, Haug LS, Becher G, Alexander J. 2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) in human hair as biomarker for dietary exposure. Biomarkers. 1999;4(4):263–71.

    Article  CAS  Google Scholar 

  39. Koutros S, Berndt SI, Sinha R, Ma X, Chatterjee N, Alavanja MC, Zheng T, Huang WY, Hayes RB, Cross AJ. Xenobiotic metabolizing gene variants, dietary heterocyclic amine intake, and risk of prostate cancer. Cancer Res. 2009;69(5):1877–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Ministry of Health of the Slovak Republic under the projects 2012/27-UKMA-4 “Study of molecular changes of selected genes and their potential role as a diagnostic and prognostic markers of prostate cancer.” and by project “CENTER OF EXCELLENCE FOR RESEARCH ON PERSONALIZED THERAPY (CEVYPET)”, code 2622012053, co-financed from EU sources and European Regional Development Fund. Data analysis was supported by the grant KEGA 003UK-4/2012. The authors are grateful to Dr N. A. Yeboah for critical reading of the manuscript and wish to thank Mrs M. Martinčeková for her technical assistance.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medical Biochemistry, Jessenius Faculty of Medicine, Comenius University in Bratislava, Malá Hora 4, 03601, Martin, Slovakia

    Marta Vilčková, Jana Jurečeková, Dušan Dobrota & Monika Kmeťová Sivoňová

  2. Department of Medical Biology, Faculty of Medicine, Safarikiensis University in Košice, Trieda SNP 1, 04066, Košice, Slovakia

    Viera Habalová & Lucia Klimčáková

  3. Division of Biomedical Physics, Department of Nuclear Physics and Biophysics, Faculty of Mathematics, Physics, and Informatics, Comenius University, Mlynská dolina F1, 84248, Bratislava, Slovakia

    Iveta Waczulíková

  4. Faculty of Medicine, Institute of Simulation and Virtual Medical Education, Comenius University, Sasinkova 4, 81104, Bratislava, Slovakia

    Peter Slezák

  5. Department of Urology, Jessenius Faculty of Medicine and UHM, Comenius University in Bratislava, Kollárová 2, 03601, Martin, Slovakia

    Ján Kliment

Authors
  1. Marta Vilčková
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jana Jurečeková
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dušan Dobrota
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Viera Habalová
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lucia Klimčáková
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Iveta Waczulíková
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Slezák
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ján Kliment
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Monika Kmeťová Sivoňová
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monika Kmeťová Sivoňová.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vilčková, M., Jurečeková, J., Dobrota, D. et al. Variation in N-acetyltransferase 2 (NAT2), smoking and risk of prostate cancer in the Slovak population. Med Oncol 31, 987 (2014). https://doi.org/10.1007/s12032-014-0987-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-014-0987-3

Keywords

Search

Navigation