Skip to main content
PMC home page
Gut logoLink to Gut
. 2000 Nov;47(5):703–709. doi: 10.1136/gut.47.5.703

Role of N-acetyltransferase polymorphisms in hepatitis B related hepatocellular carcinoma: impact of smoking on risk

M Yu 1, C Pai 1, S Yang 1, T Hsiao 1, H Chang 1, S Lin 1, Y Liaw 1, P Chen 1, C Chen 1
PMCID: PMC1728099  PMID: 11034589

Abstract

BACKGROUND—Persistent infection with hepatitis B virus (HBV) causes chronic phasic necroinflammation and regenerative proliferation in the liver. The sustained hepatocellular proliferation may render chronic HBV carriers more susceptible to the effects of environmental carcinogens. Aromatic amines are potential hepatocarcinogens in humans. N-acetyltransferase (NAT) is involved in the metabolic activation and detoxification of these compounds.
AIMS—To investigate if genetic polymorphisms in N-acetylation are related to hepatocellular carcinoma (HCC) among chronic HBV carriers.
METHODS—Genotyping of NAT1 and NAT2 was performed using polymerase chain reaction-restriction fragment length polymorphism on peripheral leucocyte DNA from 151 incident cases of HCC and 211 controls. All subjects were male, and were chronic HBV surface antigen carriers.
RESULTS—A significant association between NAT2 genetic polymorphism and HCC was observed among chronic HBV carriers who were smokers but not among those who were non-smokers. For smoking HBV carriers, the odds ratios of developing HCC for those heterozygous and homozygous for the NAT2*4 functional allele compared with those without any copies of the functional allele (reference group) were 2.67 (95% confidence interval 1.15-6.22) and 2.58 (95% confidence interval 1.04-6.43), respectively. The interaction between cigarette smoking and the presence of the NAT2*4 allele just failed to reach statistical significance (p=0.06). No association between NAT1 genotype and HCC was evident overall or within the smoking stratified subgroups.
CONCLUSIONS—Our results suggest that NAT2 activity may be particularly critical in smoking related hepatocarcinogenesis among chronic HBV carriers. Our data also indirectly support a role for tobacco smoke derived aromatic amines in the aetiology of HCC.


Keywords: genetic polymorphism; hepatocellular carcinoma; N-acetyltransferase; smoking

Full Text

The Full Text of this article is available as a PDF (146.2 KB).

Selected References

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

  1. Adamson R. H., Thorgeirsson U. P., Snyderwine E. G., Thorgeirsson S. S., Reeves J., Dalgard D. W., Takayama S., Sugimura T. Carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in nonhuman primates: induction of tumors in three macaques. Jpn J Cancer Res. 1990 Jan;81(1):10–14. doi: 10.1111/j.1349-7006.1990.tb02500.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Agúndez J. A., Olivera M., Ladero J. M., Rodriguez-Lescure A., Ledesma M. C., Diaz-Rubio M., Meyer U. A., Benítez J. Increased risk for hepatocellular carcinoma in NAT2-slow acetylators and CYP2D6-rapid metabolizers. Pharmacogenetics. 1996 Dec;6(6):501–512. doi: 10.1097/00008571-199612000-00003. [DOI] [PubMed] [Google Scholar]
  3. Ambrosone C. B., Freudenheim J. L., Graham S., Marshall J. R., Vena J. E., Brasure J. R., Michalek A. M., Laughlin R., Nemoto T., Gillenwater K. A. Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA. 1996 Nov 13;276(18):1494–1501. [PubMed] [Google Scholar]
  4. Beasley R. P. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer. 1988 May 15;61(10):1942–1956. doi: 10.1002/1097-0142(19880515)61:10<1942::aid-cncr2820611003>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. 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]
  7. 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]
  8. Benichou J. Methods of adjustment for estimating the attributable risk in case-control studies: a review. Stat Med. 1991 Nov;10(11):1753–1773. doi: 10.1002/sim.4780101113. [DOI] [PubMed] [Google Scholar]
  9. Berman J. J. Cell proliferation and the aetiology of hepatocellular carcinoma. J Hepatol. 1988 Dec;7(3):305–309. doi: 10.1016/s0168-8278(88)80002-3. [DOI] [PubMed] [Google Scholar]
  10. Blum M., Demierre A., Grant D. M., Heim M., Meyer U. A. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5237–5241. doi: 10.1073/pnas.88.12.5237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. Cascorbi I., Brockmöller J., Mrozikiewicz P. M., Bauer S., Loddenkemper R., Roots I. Homozygous rapid arylamine N-acetyltransferase (NAT2) genotype as a susceptibility factor for lung cancer. Cancer Res. 1996 Sep 1;56(17):3961–3966. [PubMed] [Google Scholar]
  14. Chen C. J., Yu M. W., Liaw Y. F., Wang L. W., Chiamprasert S., Matin F., Hirvonen A., Bell D. A., Santella R. M. Chronic hepatitis B carriers with null genotypes of glutathione S-transferase M1 and T1 polymorphisms who are exposed to aflatoxin are at increased risk of hepatocellular carcinoma. Am J Hum Genet. 1996 Jul;59(1):128–134. [PMC free article] [PubMed] [Google Scholar]
  15. Chen J., Stampfer M. J., Hough H. L., Garcia-Closas M., Willett W. C., Hennekens C. H., Kelsey K. T., Hunter D. J. A prospective study of N-acetyltransferase genotype, red meat intake, and risk of colorectal cancer. Cancer Res. 1998 Aug 1;58(15):3307–3311. [PubMed] [Google Scholar]
  16. Chen P. J., Chen D. S. Hepatitis B virus infection and hepatocellular carcinoma: molecular genetics and clinical perspectives. Semin Liver Dis. 1999;19(3):253–262. doi: 10.1055/s-2007-1007115. [DOI] [PubMed] [Google Scholar]
  17. Cohen S. M., Ellwein L. B. Cell proliferation in carcinogenesis. Science. 1990 Aug 31;249(4972):1007–1011. doi: 10.1126/science.2204108. [DOI] [PubMed] [Google Scholar]
  18. De Flora S., Hietanen E., Bartsch H., Camoirano A., Izzotti A., Bagnasco M., Millman I. Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. Carcinogenesis. 1989 Jun;10(6):1099–1106. doi: 10.1093/carcin/10.6.1099. [DOI] [PubMed] [Google Scholar]
  19. De Flora S., Romano M., Basso C., Serra D., Astengo M., Picciotto A. Metabolic activation of hepatocarcinogens in chronic hepatitis B. Mutat Res. 1985 Nov;144(3):213–219. doi: 10.1016/0165-7992(85)90143-5. [DOI] [PubMed] [Google Scholar]
  20. Eaton D. L., Gallagher E. P., Bammler T. K., Kunze K. L. Role of cytochrome P4501A2 in chemical carcinogenesis: implications for human variability in expression and enzyme activity. Pharmacogenetics. 1995 Oct;5(5):259–274. doi: 10.1097/00008571-199510000-00001. [DOI] [PubMed] [Google Scholar]
  21. Hein D. W., Doll M. A., Rustan T. D., Ferguson R. J. Metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides by 16 recombinant human NAT2 allozymes: effects of 7 specific NAT2 nucleic acid substitutions. Cancer Res. 1995 Aug 15;55(16):3531–3536. [PubMed] [Google Scholar]
  22. Hein D. W., Doll M. A., Rustan T. D., Gray K., Feng Y., Ferguson R. J., Grant D. M. Metabolic activation and deactivation of arylamine carcinogens by recombinant human NAT1 and polymorphic NAT2 acetyltransferases. Carcinogenesis. 1993 Aug;14(8):1633–1638. doi: 10.1093/carcin/14.8.1633. [DOI] [PubMed] [Google Scholar]
  23. Kato T., Ohgaki H., Hasegawa H., Sato S., Takayama S., Sugimura T. Carcinogenicity in rats of a mutagenic compound, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. Carcinogenesis. 1988 Jan;9(1):71–73. doi: 10.1093/carcin/9.1.71. [DOI] [PubMed] [Google Scholar]
  24. Land S. J., Zukowski K., Lee M. S., Debiec-Rychter M., King C. M., Wang C. Y. Metabolism of aromatic amines: relationships of N-acetylation, O-acetylation, N,O-acetyltransfer and deacetylation in human liver and urinary bladder. Carcinogenesis. 1989 Apr;10(4):727–731. doi: 10.1093/carcin/10.4.727. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Marsili M. A., Robinson M. K., Truitt G. A., Wheelock E. F. Elimination of L5178Y cells from tumor-dormant DBA/2 mice by specific active immunotherapy. Cancer Res. 1983 Jan;43(1):15–21. [PubMed] [Google Scholar]
  27. Ohgaki H., Hasegawa H., Suenaga M., Sato S., Takayama S., Sugimura T. Carcinogenicity in mice of a mutagenic compound, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) from cooked foods. Carcinogenesis. 1987 May;8(5):665–668. doi: 10.1093/carcin/8.5.665. [DOI] [PubMed] [Google Scholar]
  28. Ohgaki H., Kusama K., Matsukura N., Morino K., Hasegawa H., Sato S., Takayama S., Sugimura T. Carcinogenicity in mice of a mutagenic compound, 2-amino-3-methylimidazo[4,5-f]quinoline, from broiled sardine, cooked beef and beef extract. Carcinogenesis. 1984 Jul;5(7):921–924. doi: 10.1093/carcin/5.7.921. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Poirier M. C., Fullerton N. F., Smith B. A., Beland F. A. DNA adduct formation and tumorigenesis in mice during the chronic administration of 4-aminobiphenyl at multiple dose levels. Carcinogenesis. 1995 Dec;16(12):2917–2921. doi: 10.1093/carcin/16.12.2917. [DOI] [PubMed] [Google Scholar]
  31. Takayama S., Nakatsuru Y., Masuda M., Ohgaki H., Sato S., Sugimura T. Demonstration of carcinogenicity in F344 rats of 2-amino-3-methyl-imidazo[4,5-f]quinoline from broiled sardine, fried beef and beef extract. Gan. 1984 Jun;75(6):467–470. [PubMed] [Google Scholar]
  32. Talaska G., al-Juburi A. Z., Kadlubar F. F. Smoking related carcinogen-DNA adducts in biopsy samples of human urinary bladder: identification of N-(deoxyguanosin-8-yl)-4-aminobiphenyl as a major adduct. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5350–5354. doi: 10.1073/pnas.88.12.5350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. 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]
  34. Turesky R. J., Lang N. P., Butler M. A., Teitel C. H., Kadlubar F. F. Metabolic activation of carcinogenic heterocyclic aromatic amines by human liver and colon. Carcinogenesis. 1991 Oct;12(10):1839–1845. doi: 10.1093/carcin/12.10.1839. [DOI] [PubMed] [Google Scholar]
  35. Wang L. Y., Chen C. J., Zhang Y. J., Tsai W. Y., Lee P. H., Feitelson M. A., Lee C. S., Santella R. M. 4-Aminobiphenyl DNA damage in liver tissue of hepatocellular carcinoma patients and controls. Am J Epidemiol. 1998 Feb 1;147(3):315–323. doi: 10.1093/oxfordjournals.aje.a009452. [DOI] [PubMed] [Google Scholar]
  36. Yamashita M., Wakabayashi K., Nagao M., Sato S., Yamaizumi Z., Takahashi M., Kinae N., Tomita I., Sugimura T. Detection of 2-amino-3-methylimidazo[4,5-f]quinoline in cigarette smoke condensate. Jpn J Cancer Res. 1986 May;77(5):419–422. [PubMed] [Google Scholar]
  37. Yu M. C., Tong M. J., Govindarajan S., Henderson B. E. Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California. J Natl Cancer Inst. 1991 Dec 18;83(24):1820–1826. doi: 10.1093/jnci/83.24.1820. [DOI] [PubMed] [Google Scholar]
  38. Yu M. W., Chen C. J. Hepatitis B and C viruses in the development of hepatocellular carcinoma. Crit Rev Oncol Hematol. 1994 Oct;17(2):71–91. doi: 10.1016/1040-8428(94)90020-5. [DOI] [PubMed] [Google Scholar]
  39. Yu M. W., Chiu Y. H., Chiang Y. C., Chen C. H., Lee T. H., Santella R. M., Chern H. D., Liaw Y. F., Chen C. J. Plasma carotenoids, glutathione S-transferase M1 and T1 genetic polymorphisms, and risk of hepatocellular carcinoma: independent and interactive effects. Am J Epidemiol. 1999 Apr 1;149(7):621–629. doi: 10.1093/oxfordjournals.aje.a009862. [DOI] [PubMed] [Google Scholar]
  40. Yu M. W., Chiu Y. H., Yang S. Y., Santella R. M., Chern H. D., Liaw Y. F., Chen C. J. Cytochrome P450 1A1 genetic polymorphisms and risk of hepatocellular carcinoma among chronic hepatitis B carriers. Br J Cancer. 1999 May;80(3-4):598–603. doi: 10.1038/sj.bjc.6690397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Yu M. W., Gladek-Yarborough A., Chiamprasert S., Santella R. M., Liaw Y. F., Chen C. J. Cytochrome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. Gastroenterology. 1995 Oct;109(4):1266–1273. doi: 10.1016/0016-5085(95)90587-1. [DOI] [PubMed] [Google Scholar]
  42. Yu M. W., Horng I. S., Hsu K. H., Chiang Y. C., Liaw Y. F., Chen C. J. Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection. Am J Epidemiol. 1999 Aug 15;150(4):367–374. doi: 10.1093/oxfordjournals.aje.a010016. [DOI] [PubMed] [Google Scholar]
  43. Yu M. W., Hsieh H. H., Pan W. H., Yang C. S., CHen C. J. Vegetable consumption, serum retinol level, and risk of hepatocellular carcinoma. Cancer Res. 1995 Mar 15;55(6):1301–1305. [PubMed] [Google Scholar]
  44. Yu M. W., Lien J. P., Chiu Y. H., Santella R. M., Liaw Y. F., Chen C. J. Effect of aflatoxin metabolism and DNA adduct formation on hepatocellular carcinoma among chronic hepatitis B carriers in Taiwan. J Hepatol. 1997 Aug;27(2):320–330. doi: 10.1016/s0168-8278(97)80178-x. [DOI] [PubMed] [Google Scholar]
  45. Yu M. W., Yang S. Y., Chiu Y. H., Chiang Y. C., Liaw Y. F., Chen C. J. A p53 genetic polymorphism as a modulator of hepatocellular carcinoma risk in relation to chronic liver disease, familial tendency, and cigarette smoking in hepatitis B carriers. Hepatology. 1999 Mar;29(3):697–702. doi: 10.1002/hep.510290330. [DOI] [PubMed] [Google Scholar]
  46. Yu M. W., You S. L., Chang A. S., Lu S. N., Liaw Y. F., Chen C. J. Association between hepatitis C virus antibodies and hepatocellular carcinoma in Taiwan. Cancer Res. 1991 Oct 15;51(20):5621–5625. [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES