Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Oct;81(3):537–541. doi: 10.1038/sj.bjc.6690727

Genetic polymorphisms of N-acetyltransferase 1 and 2 and risk of cigarette smoking-related bladder cancer

F-I Hsieh 1, Y-S Pu 2, H-D Chern 3, L-I Hsu 1, H-Y Chiou 4, C-J Chen 1
PMCID: PMC2362925  PMID: 10507782

Abstract

Aromatic amines from cigarette smoking or occupational exposure, recognized risk factors for bladder cancer, are metabolized by N-acetyltransferases (NAT). This study examined the association of (NAT) 1 and 2 genotypes with the risk of smoking-related bladder cancer. A total of 74 pathologically confirmed bladder cancer patients and 184 controls were serially recruited from the National Taiwan University Hospital. History of cigarette smoking and other risk factors for bladder cancer was obtained through standardized questionnaire interview. Peripheral blood lymphocytes were collected from each subject and genotyped for NAT1 and NAT2 by DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Allele frequency distributions of NAT1 and NAT2 were similar between cases and controls. There was a significant dose–response relationship between the risk of bladder cancer and the quantity and duration of cigarette smoking. The biological gradients were significant among subjects carrying NAT1*10 allele or NAT2 slow acetylators, but not among NAT2 rapid acetylators without NAT1*10 allele. The results are consistent with the hypothesis that NAT1 and NAT2 might modulate the susceptibility to bladder cancer associated with cigarette smoking. © 1999 Cancer Research Campaign

Keywords: N-acetyltransferase 1, N-acetyltransferase 2, cigarette smoking, bladder cancer

Full Text

The Full Text of this article is available as a PDF (58.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Augustine A., Hebert J. R., Kabat G. C., Wynder E. L. Bladder cancer in relation to cigarette smoking. Cancer Res. 1988 Aug 1;48(15):4405–4408. [PubMed] [Google Scholar]
  2. Bartsch H., Malaveille C., Friesen M., Kadlubar F. F., Vineis P. Black (air-cured) and blond (flue-cured) tobacco cancer risk. IV: Molecular dosimetry studies implicate aromatic amines as bladder carcinogens. Eur J Cancer. 1993;29A(8):1199–1207. doi: 10.1016/s0959-8049(05)80315-6. [DOI] [PubMed] [Google Scholar]
  3. Bell D. A., Badawi A. F., Lang N. P., Ilett K. F., Kadlubar F. F., Hirvonen A. Polymorphism in the N-acetyltransferase 1 (NAT1) polyadenylation signal: association of NAT1*10 allele with higher N-acetylation activity in bladder and colon tissue. Cancer Res. 1995 Nov 15;55(22):5226–5229. [PubMed] [Google Scholar]
  4. Bell D. A., Stephens E. A., Castranio T., Umbach D. M., Watson M., Deakin M., Elder J., Hendrickse C., Duncan H., Strange R. C. Polyadenylation polymorphism in the acetyltransferase 1 gene (NAT1) increases risk of colorectal cancer. Cancer Res. 1995 Aug 15;55(16):3537–3542. [PubMed] [Google Scholar]
  5. Bell D. A., Taylor J. A., Butler M. A., Stephens E. A., Wiest J., Brubaker L. H., Kadlubar F. F., Lucier G. W. Genotype/phenotype discordance for human arylamine N-acetyltransferase (NAT2) reveals a new slow-acetylator allele common in African-Americans. Carcinogenesis. 1993 Aug;14(8):1689–1692. doi: 10.1093/carcin/14.8.1689. [DOI] [PubMed] [Google Scholar]
  6. Brockmöller J., Cascorbi I., Kerb R., Roots I. Combined analysis of inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1, microsomal epoxide hydrolase, and cytochrome P450 enzymes as modulators of bladder cancer risk. Cancer Res. 1996 Sep 1;56(17):3915–3925. [PubMed] [Google Scholar]
  7. Burch J. D., Rohan T. E., Howe G. R., Risch H. A., Hill G. B., Steele R., Miller A. B. Risk of bladder cancer by source and type of tobacco exposure: a case-control study. Int J Cancer. 1989 Oct 15;44(4):622–628. doi: 10.1002/ijc.2910440411. [DOI] [PubMed] [Google Scholar]
  8. Butler M. A., Iwasaki M., Guengerich F. P., Kadlubar F. F. Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7696–7700. doi: 10.1073/pnas.86.20.7696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chiou H. Y., Hsueh Y. M., Liaw K. F., Horng S. F., Chiang M. H., Pu Y. S., Lin J. S., Huang C. H., Chen C. J. Incidence of internal cancers and ingested inorganic arsenic: a seven-year follow-up study in Taiwan. Cancer Res. 1995 Mar 15;55(6):1296–1300. [PubMed] [Google Scholar]
  10. Claude J., Kunze E., Frentzel-Beyme R., Paczkowski K., Schneider J., Schubert H. Life-style and occupational risk factors in cancer of the lower urinary tract. Am J Epidemiol. 1986 Oct;124(4):578–589. doi: 10.1093/oxfordjournals.aje.a114430. [DOI] [PubMed] [Google Scholar]
  11. Fleming C. M., Persad R., Kaisary A., Smith P., Adedoyin A., Porter J., Wilkinson G. R., Branch R. A. Low activity of dapsone N-hydroxylation as a susceptibility risk factor in aggressive bladder cancer. Pharmacogenetics. 1994 Aug;4(4):199–207. doi: 10.1097/00008571-199408000-00004. [DOI] [PubMed] [Google Scholar]
  12. Frederickson S. M., Messing E. M., Reznikoff C. A., Swaminathan S. Relationship between in vivo acetylator phenotypes and cytosolic N-acetyltransferase and O-acetyltransferase activities in human uroepithelial cells. Cancer Epidemiol Biomarkers Prev. 1994 Jan-Feb;3(1):25–32. [PubMed] [Google Scholar]
  13. Jensen O. M., Wahrendorf J., Blettner M., Knudsen J. B., Sørensen B. L. The Copenhagen case-control study of bladder cancer: role of smoking in invasive and non-invasive bladder tumours. J Epidemiol Community Health. 1987 Mar;41(1):30–36. doi: 10.1136/jech.41.1.30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kirlin W. G., Trinidad A., Yerokun T., Ogolla F., Ferguson R. J., Andrews A. F., Brady P. K., Hein D. W. Polymorphic expression of acetyl coenzyme A-dependent arylamine N-acetyltransferase and acetyl coenzyme A-dependent O-acetyltransferase-mediated activation of N-hydroxyarylamines by human bladder cytosol. Cancer Res. 1989 May 1;49(9):2448–2454. [PubMed] [Google Scholar]
  15. Lin H. J., Han C. Y., Lin B. K., Hardy S. Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, blacks, Hispanics, and whites: application to metabolic epidemiology. Am J Hum Genet. 1993 Apr;52(4):827–834. [PMC free article] [PubMed] [Google Scholar]
  16. López-Abente G., González C. A., Errezola M., Escolar A., Izarzugaza I., Nebot M., Riboli E. Tobacco smoke inhalation pattern, tobacco type, and bladder cancer in Spain. Am J Epidemiol. 1991 Oct 15;134(8):830–839. doi: 10.1093/oxfordjournals.aje.a116158. [DOI] [PubMed] [Google Scholar]
  17. Okkels H., Sigsgaard T., Wolf H., Autrup H. Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) polymorphisms in susceptibility to bladder cancer: the influence of smoking. Cancer Epidemiol Biomarkers Prev. 1997 Apr;6(4):225–231. [PubMed] [Google Scholar]
  18. Risch A., Wallace D. M., Bathers S., Sim E. Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer. Hum Mol Genet. 1995 Feb;4(2):231–236. doi: 10.1093/hmg/4.2.231. [DOI] [PubMed] [Google Scholar]
  19. Schairer C., Hartge P., Hoover R. N., Silverman D. T. Racial differences in bladder cancer risk: a case-control study. Am J Epidemiol. 1988 Nov;128(5):1027–1037. doi: 10.1093/oxfordjournals.aje.a115047. [DOI] [PubMed] [Google Scholar]
  20. Skipper P. L., Tannenbaum S. R. Molecular dosimetry of aromatic amines in human populations. Environ Health Perspect. 1994 Oct;102 (Suppl 6):17–21. doi: 10.1289/ehp.94102s617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Smith B. J., DeBruin L., Josephy P. D., Eling T. E. Mutagenic activation of benzidine requires prior bacterial acetylation and subsequent conversion by prostaglandin H synthase to 4-nitro-4'-(acetylamino)biphenyl. Chem Res Toxicol. 1992 May-Jun;5(3):431–439. doi: 10.1021/tx00027a018. [DOI] [PubMed] [Google Scholar]
  22. Taylor J. A., Umbach D. M., Stephens E., Castranio T., Paulson D., Robertson C., Mohler J. L., Bell D. A. The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction. Cancer Res. 1998 Aug 15;58(16):3603–3610. [PubMed] [Google Scholar]
  23. Vatsis K. P., Weber W. W., Bell D. A., Dupret J. M., Evans D. A., Grant D. M., Hein D. W., Lin H. J., Meyer U. A., Relling M. V. Nomenclature for N-acetyltransferases. Pharmacogenetics. 1995 Feb;5(1):1–17. doi: 10.1097/00008571-199502000-00001. [DOI] [PubMed] [Google Scholar]
  24. Vatsis K. P., Weber W. W. Structural heterogeneity of Caucasian N-acetyltransferase at the NAT1 gene locus. Arch Biochem Biophys. 1993 Feb 15;301(1):71–76. doi: 10.1006/abbi.1993.1116. [DOI] [PubMed] [Google Scholar]
  25. Vineis P., Bartsch H., Caporaso N., Harrington A. M., Kadlubar F. F., Landi M. T., Malaveille C., Shields P. G., Skipper P., Talaska G. Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens. Nature. 1994 May 12;369(6476):154–156. doi: 10.1038/369154a0. [DOI] [PubMed] [Google Scholar]
  26. Weber W. W., Vatsis K. P. Individual variability in p-aminobenzoic acid N-acetylation by human N-acetyltransferase (NAT1) of peripheral blood. Pharmacogenetics. 1993 Aug;3(4):209–212. doi: 10.1097/00008571-199308000-00006. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES