Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

Oncogene volume 25, pages 1649–1658 (2006)Cite this article

Abstract

A role for the N-acetyltransferase 2 (NAT2) genetic polymorphism in cancer risk has been the subject of numerous studies. Although comprehensive reviews of the NAT2 acetylation polymorphism have been published elsewhere, the objective of this paper is to briefly highlight some important features of the NAT2 acetylation polymorphism that are not universally accepted to better understand the role of NAT2 polymorphism in carcinogenic risk assessment. NAT2 slow acetylator phenotype(s) infer a consistent and robust increase in urinary bladder cancer risk following exposures to aromatic amine carcinogens. However, identification of specific carcinogens is important as the effect of NAT2 polymorphism on urinary bladder cancer differs dramatically between monoarylamines and diarylamines. Misclassifications of carcinogen exposure and NAT2 genotype/phenotype confound evidence for a real biological effect. Functional understanding of the effects of NAT2 genetic polymorphisms on metabolism and genotoxicity, tissue-specific expression and the elucidation of the molecular mechanisms responsible are critical for the interpretation of previous and future human molecular epidemiology investigations into the role of NAT2 polymorphism on cancer risk. Although associations have been reported for various cancers, this paper focuses on urinary bladder cancer, a cancer in which a role for NAT2 polymorphism was first proposed and for which evidence is accumulating that the effect is biologically significant with important public health implications.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Abe M, Deguchi T, Suzuki T . (1993). Biochem Biophys Res Commun 191: 811–816.

  • Agundez JA, Menaya JG, Tejeda R, Lago F, Chavez M, Benitez J . (1996). Pharmacogenetics 6: 465–472.

  • Airoldi L, Orsi F, Magagnotti C, Coda R, Randone D, Casetta G et al. (2002). Carcinogenesis 23: 861–866.

  • Anitha A, Banerjee M . (2003). Int J Mol Med 11: 125–131.

  • Badawi AF, Hirvonen A, Bell DA, Lang NP, Kadlubar FF . (1995). Cancer Res 55: 5230–5237.

  • Blum M, Demierre A, Grant DM, Heim M, Meyer UA . (1991). Proc Natl Acad Sci USA 88: 5237–5241.

  • Blum M, Grant DM, Demierre A, Meyer UA . (1989). Proc Natl Acad Sci USA 86: 9554–9557.

  • Blum M, Grant DM, McBride W, Heim M, Meyer UA . (1990). DNA Cell Biol 9: 193–203.

  • Bolt HM, Selinski S, Dannappel D, Blaszkewicz M, Golka K . (2005). Arch Toxicol 79: 196–200.

  • Boukouvala S, Sim E . (2005). Basic Clin Pharmacol Toxicol 96: 343–351.

  • Brockmoller J, Cascorbi I, Kerb R, Roots I . (1996). Cancer Res 56: 3915–3925.

  • Carreon T, Ruder AM, Schulte PA, Hayes RB, Rothman N, Waters M et al. (2006). Int J Cancer 118: 161–168.

  • Cartwright RA, Glashan RW, Rogers HJ, Ahmad RA, Barham-Hall D, Higgins E et al. (1982). Lancet 2: 842–845.

  • Cascorbi I, Brockmoller J, Bauer S, Reum T, Roots I . (1996). Pharmacogenetics 6: 257–259.

  • Cascorbi I, Brockmoller J, Mrozikiewicz PM, Muller A, Roots I . (1999). Drug Metab Rev 31: 489–502.

  • Cascorbi I, Drakoulis N, Brockmoller J, Maurer A, Sperling K, Roots I . (1995). Am J Hum Genet 57: 581–592.

  • Cascorbi I, Roots I . (1999). Pharmacogenetics 9: 123–127.

  • Chapron DJ, Kramer PA, Mercik SA . (1980). Clin Pharmacol Ther 27: 104–113.

  • Chung JG, Levy GN, Weber WW . (1993). Drug Metab Dispos 21: 1057–1063.

  • Cribb AE, Isbrucker R, Levatte T, Tsui B, Gillespie CT, Renton KW . (1994). Pharmacogenetics 4: 166–170.

  • Deguchi T . (1992). J Biol Chem 267: 18140–18147.

  • Deguchi T, Mashimo M, Suzuki T . (1990). J Biol Chem 265: 12757–12760.

  • Deitz AC, Rothman N, Rebbeck TR, Hayes RB, Chow WH, Zheng W et al. (2004). Cancer Epidemiol Biomarkers Prev 13: 1543–1546.

  • Deitz AC, Zheng W, Leff MA, Gross M, Wen WQ, Doll MA et al. (2000). Cancer Epidemiol Biomarkers Prev 9: 905–910.

  • Delomenie C, Sica L, Grant DM, Krishnamoorthy R, Dupret JM . (1996). Pharmacogenetics 6: 177–185.

  • Dewan A, Chattopadhyay P, Kulkarni PK . (1995). Indian J Cancer 32: 15–19.

  • Doll MA, Hein DW . (1995). Pharmacogenetics 5: 247–251.

  • Dupret JM, Grant DM . (1992). J Biol Chem 267: 7381–7385.

  • Dupret JM, Rodrigues-Lima F . (2005). Curr Med Chem 12: 311–318.

  • Ebisawa T, Deguchi T . (1991). Biochem Biophys Res Commun 177: 1252–1257.

  • El Desoky ES, AbdelSalam YM, Salama RH, El Akkad MA, Atanasova S, von Ahsen N et al. (2005). Ther Drug Monit 27: 297–304.

  • Ferguson RJ, Doll MA, Rustan TD, Gray K, Hein DW . (1994). Drug Metab Dispos 22: 371–376.

  • Ferguson RJ, Doll MA, Rustan TD, Hein DW . (1996). Pharmacogenetics 6: 55–66.

  • Filiadis IF, Georgiou I, Alamanos Y, Kranas V, Giannakopoulos X, Lolis D . (1999). J Urol 161: 1672–1675.

  • Frederickson SM, Hatcher JF, Reznikoff CA, Swaminathan S . (1992). Carcinogenesis 13: 955–961.

  • Frederickson SM, Messing EM, Reznikoff CA, Swaminathan S . (1994). Cancer Epidemiol Biomarkers Prev 3: 25–32.

  • Fretland AJ, Doll MA, Leff MA, Hein DW . (2001). Pharmacogenetics 11: 511–520.

  • Gago-Dominguez M, Bell DA, Watson MA, Yuan JM, Castelao JE, Hein DW et al. (2003). Carcinogenesis 24: 483–489.

  • Garcia-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW et al. (2005). Lancet 366: 649–659.

  • Giannakopoulos X, Charalabopoulos K, Baltogiannis D, Chatzikiriakidou A, Alamanos Y, Georgiou I et al. (2002). Anticancer Res 22: 3801–3804.

  • Golka K, Prior V, Blaszkewicz M, Bolt HM . (2002). Toxicol Lett 128: 229–241.

  • Grant DM, Hughes NC, Janezic SA, Goodfellow GH, Chen HJ, Gaedigk A et al. (1997). Mutat Res 376: 61–70.

  • Grant DM, Morike K, Eichelbaum M, Meyer UA . (1990). J Clin Invest 85: 968–972.

  • Grant DM, Tang BK, Kalow W . (2004). Br J Clin Pharmacol 58: S788–S793.

  • Green J, Banks E, Berrington A, Darby S, Deo H, Newton R . (2000). Br J Cancer 83: 412–417.

  • Gross M, Kruisselbrink T, Anderson K, Lang N, McGovern P, Delongchamp R et al. (1999). Cancer Epidemiol Biomarkers Prev 8: 683–692.

  • Gu J, Liang D, Wang Y, Lu C, Wu X . (2005). Mutat Res 581: 97–104.

  • Hanssen HP, Agarwal DP, Goedde HW, Bucher H, Huland H, Brachmann W et al. (1985). Eur Urol 11: 263–266.

  • Hao GY, Zhang WD, Chen YH, Zhang DX, Zhang YH . (2004). Zhonghua Zhong Liu Za Zhi 26: 283–286.

  • Hayes RB, Bi W, Rothman N, Broly F, Caporaso N, Feng P et al. (1993). Carcinogenesis 14: 675–678.

  • Hearse DJ, Weber WW . (1973). Biochem J 132: 519–526.

  • Hein DW . (1988). Biochim Biophys Acta 948: 37–66.

  • Hein DW . (2002). Mutat Res 506–507: 65–77.

  • Hein DW, Doll MA, Fretland AJ, Gray K, Deitz AC, Feng Y et al. (1997). Mutat Res 376: 101–106.

  • Hein DW, Doll MA, Fretland AJ, Leff MA, Webb SJ, Xiao GH et al. (2000). Cancer Epidemiol Biomarkers Prev 9: 29–42.

  • Hein DW, Doll MA, Gray K, Rustan TD, Ferguson RJ . (1993a). Cancer Res 53: 509–514.

  • Hein DW, Doll MA, Nerland DE, Fretland AJ . (2006). Mol Carcinogenesis (in press).

  • Hein DW, Doll MA, Rustan TD, Ferguson RJ . (1995). Cancer Res 55: 3531–3536.

  • Hein DW, Doll MA, Rustan TD, Gray K, Feng Y, Ferguson RJ et al. (1993b). Carcinogenesis 14: 1633–1638.

  • Hein DW, Doll MA, Rustan TD, Gray K, Ferguson RJ, Feng Y . (1994a). Toxicol Appl Pharmacol 124: 16–24.

  • Hein DW, Doll MA, Xiao GH, Feng Y . (2003). Pharmacogenetics 13: 159–167.

  • Hein DW, Ferguson RJ, Doll MA, Rustan TD, Gray K . (1994b). Hum Mol Genet 3: 729–734.

  • Hein DW, Kirlin WG, Ferguson RJ, Weber WW . (1985). J Pharmacol Exp Ther 234: 358–364.

  • Hein DW, Rustan TD, Bucher KD, Martin WJ, Furman EJ . (1991a). Drug Metab Dispos 19: 933–937.

  • Hein DW, Rustan TD, Bucher KD, Miller LS . (1991b). J Pharmacol Exp Ther 259: 699–704.

  • Hein DW, Trinidad A, Yerokun T, Ferguson RJ, Kirlin WG, Weber WW . (1988). Drug Metab Dispos 16: 341–347.

  • Hickman D, Palamanda JR, Unadkat JD, Sim E . (1995). Biochem Pharmacol 50: 697–703.

  • Hickman D, Pope J, Patil SD, Fakis G, Smelt V, Stanley LA et al. (1998). Gut 42: 402–409.

  • Hickman D, Risch A, Buckle V, Spurr NK, Jeremiah SJ, McCarthy A et al. (1994). Biochem J 297 (Part 3): 441–445.

  • Horai Y, Fujita K, Ishizaki T . (1989). Eur J Clin Pharmacol 37: 581–587.

  • Hsieh FI, Pu YS, Chern HD, Hsu LI, Chiou HY, Chen CJ . (1999). Br J Cancer 81: 537–541.

  • Hughes HB, Biehl JP, Jones AP, Scmidt LH . (1954). Am Rev Res Dis 70: 266–273.

  • Hung RJ, Boffetta P, Brennan P, Malaveille C, Hautefeuille A, Donato F et al. (2004). Int J Cancer 110: 598–604.

  • Ilett KF, Ingram DM, Carpenter DS, Teitel CH, Lang NP, Kadlubar FF et al. (1994). Biochem Pharmacol 47: 914–917.

  • Ilett KF, Reeves PT, Minchin RF, Kinnear BF, Watson HF, Kadlubar FF . (1991). Carcinogenesis 12: 1465–1469.

  • Ishizu S, Hashida C, Hanaoka T, Maeda K, Ohishi Y . (1995). Jpn J Cancer Res 86: 1179–1181.

  • Jaskula-Sztul R, Sokolowski W, Gajecka M, Szyfter K . (2001). J Appl Genet 42: 223–231.

  • Jenne JW . (1965). J Clin Invest 44: 1992–2002.

  • Kaisary A, Smith P, Jaczq E, McAllister CB, Wilkinson GR, Ray WA et al. (1987). Cancer Res 47: 5488–5493.

  • Karakaya AE, Cok I, Sardas S, Gogus O, Sardas OS . (1986). Hum Toxicol 5: 333–335.

  • Kim WJ, Lee HL, Lee SC, Kim YT, Kim H . (2000). J Urol 164: 209–213.

  • Kirlin WG, Ogolla F, Andrews AF, Trinidad A, Ferguson RJ, Yerokun T et al. (1991). Cancer Res 51: 549–555.

  • Kirlin WG, Trinidad A, Yerokun T, Ogolla F, Ferguson RJ, Andrews AF et al. (1989). Cancer Res 49: 2448–2454.

  • Ladero JM, Kwok CK, Jara C, Fernandez L, Silmi AM, Tapia D et al. (1985). Ann Clin Res 17: 96–99.

  • Lan Q, Rothman N, Chow WH, Lissowska J, Doll MA, Xiao GH et al. (2003). Cancer Epidemiol Biomarkers Prev 12: 384–386.

  • Lee EJ, Lee LK . (1982). Br J Clin Pharmacol 13: 375–378.

  • Lee SY, Lee KA, Ki CS, Kwon OJ, Kim HJ, Chung MP et al. (2002). Clin Chem 48: 775–777.

  • Leff MA, Fretland AJ, Doll MA, Hein DW . (1999). J Biol Chem 274: 34519–34522.

  • Loktionov A, Moore W, Spencer SP, Vorster H, Nell T, O'Neill IK et al. (2002). Cancer Detect Prev 26: 15–22.

  • Lorenzo B, Reidenberg MM . (1989). Br J Clin Pharmacol 28: 207–208.

  • Lower Jr GM, Nilsson T, Nelson CE, Wolf H, Gamsky TE, Bryan GT . (1979). Environ Health Perspect 29: 71–79.

  • Luceri F, Pieraccini G, Moneti G, Dolara P . (1993). Toxicol Ind Health 9: 405–413.

  • Ma QW, Lin GF, Chen JG, Xiang CQ, Guo WC, Golka K et al. (2004). Biomed Environ Sci 17: 291–298.

  • Martell KJ, Vatsis KP, Weber WW . (1991). Mol Pharmacol 40: 218–227.

  • Matas N, Thygesen P, Stacey M, Risch A, Sim E . (1997). Cytogenet Cell Genet 77: 290–295.

  • Miller ME, Cosgriff JM . (1983). J Urol 130: 65–66.

  • Minchin RF, Reeves PT, Teitel CH, McManus ME, Mojarrabi B, Ilett KF et al. (1992). Biochem Biophys Res Commun 185: 839–844.

  • Mittal RD, Srivastava DS, Mandhani A . (2004). Int Braz J Urol 30: 279–285 (discussion 285–288).

  • Mommsen S, Wolf H . (1985). Scand J Urol Nephrol 19: 203–204.

  • Nagata K, Ozawa S, Miyata M, Shimada M, Yamazoe Y, Kato R . (1994). Pharmacogenetics 4: 91–100.

  • Okkels H, Sigsgaard T, Wolf H, Autrup H . (1997). Cancer Epidemiol Biomarkers Prev 6: 225–231.

  • O'Neil WM, Drobitch RK, MacArthur RD, Farrough MJ, Doll MA, Fretland AJ et al. (2000). Pharmacogenetics 10: 171–182.

  • Ozawa S, Abu-Zeid M, Kawakubo Y, Toyama S, Yamazoe Y, Kato R . (1990). Carcinogenesis 11: 2137–2144.

  • Pacifici GM, Bencini C, Rane A . (1986). Pharmacology 32: 283–291.

  • Palmiotto G, Pieraccini G, Moneti G, Dolara P . (2001). Chemosphere 43: 355–361.

  • Parkin DP, Vandenplas S, Botha FJ, Vandenplas ML, Seifart HI, van Helden PD et al. (1997). Am J Respir Crit Care Med 155: 1717–1722.

  • Peluso M, Airoldi L, Armelle M, Martone T, Coda R, Malaveille C et al. (1998). Cancer Epidemiol Biomarkers Prev 7: 341–346.

  • Pink JC, Messing EM, Reznikoff CA, Bryan GT, Swaminathan S . (1992). Drug Metab Dispos 20: 559–565.

  • Probst-Hensch NM, Bell DA, Watson MA, Skipper PL, Tannenbaum SR, Chan KK et al. (2000). Cancer Epidemiol Biomarkers Prev 9: 619–623.

  • Reilly TP, Lash LH, Doll MA, Hein DW, Woster PM, Svensson CK . (2000). J Invest Dermatol 114: 1164–1173.

  • Risch A, Wallace DM, Bathers S, Sim E . (1995). Hum Mol Genet 4: 231–236.

  • Rodrigues-Lima F, Delomenie C, Goodfellow GH, Grant DM, Dupret JM . (2001). Biochem J 356: 327–334.

  • Rodrigues-Lima F, Dupret JM . (2002). Biochem Biophys Res Commun 291: 116–123.

  • Rothman N, Bhatnagar VK, Hayes RB, Zenser TV, Kashyap SK, Butler MA et al. (1996). Proc Natl Acad Sci USA 93: 5084–5089.

  • Rothman N, Stewart WF, Caporaso NE, Hayes RB . (1993). Cancer Epidemiol Biomarkers Prev 2: 299–303.

  • Sandy J, Mushtaq A, Kawamura A, Sinclair J, Sim E, Noble M . (2002). J Mol Biol 318: 1071–1083.

  • Sinclair JC, Sandy J, Delgoda R, Sim E, Noble ME . (2000). Nat Struct Biol 7: 560–564.

  • Smith CA, Wadelius M, Gough AC, Harrison DJ, Wolf CR, Rane A . (1997). J Med Genet 34: 758–760.

  • Smith TJ, Hanna PE . (1986). Carcinogenesis 7: 697–702.

  • Stabbert R, Schafer KH, Biefel C, Rustemeier K . (2003). Rapid Commun Mass Spectrom 17: 2125–2132.

  • Stanley LA, Mills IG, Sim E . (1997). Pharmacogenetics 7: 121–130.

  • Su HJ, Guo YL, Lai MD, Huang JD, Cheng Y, Christiani DC . (1998). Pharmacogenetics 8: 187–190.

  • Sugamori KS, Wong S, Gaedigk A, Yu V, Abramovici H, Rozmahel R et al. (2003). Mol Pharmacol 64: 170–179.

  • Svensson CK, Hein DW . (2004) In: Lash LH (ed), Drug Metabolism and Transport: Molecular Methods and Mechanisms: Methods in Pharmacology and Toxicology. Humana Press: Totowa, NJ, pp 173–195.

    Google Scholar 

  • Taylor JA, Umbach DM, Stephens E, Castranio T, Paulson D, Robertson C et al. (1998). Cancer Res 58: 3603–3610.

  • Trinidad A, Kirlin WG, Ogolla F, Andrews AF, Yerokun T, Ferguson RJ et al. (1989). Drug Metab Dispos 17: 238–247.

  • Tsukino H, Nakao H, Kuroda Y, Imai H, Inatomi H, Osada Y et al. (2004). Eur J Cancer Prev 13: 509–514.

  • Turesky RJ, Lang NP, Butler MA, Teitel CH, Kadlubar FF . (1991). Carcinogenesis 12: 1839–1845.

  • van der Hel OL, Peeters PH, Hein DW, Doll MA, Grobbee DE, Kromhout D et al. (2003). Pharmacogenetics 13: 399–407.

  • Vatsis KP, Martell KJ, Weber WW . (1991). Proc Natl Acad Sci USA 88: 6333–6337.

  • Vatsis KP, Weber WW, Bell DA, Dupret JM, Evans DA, Grant DM et al. (1995). Pharmacogenetics 5: 1–17.

  • Vineis P, Alavanja M, Garte S . (2004). Int J Cancer 108: 2–7.

  • Vineis P, Bartsch H, Caporaso N, Harrington AM, Kadlubar FF, Landi MT et al. (1994). Nature 369: 154–156.

  • Vineis P, Marinelli D, Autrup H, Brockmoller J, Cascorbi I, Daly AK et al. (2001). Cancer Epidemiol Biomarkers Prev 10: 1249–1252.

  • Weber WW, Hein DW . (1985). Pharmacol Rev 37: 25–79.

  • Windmill KF, Gaedigk A, Hall PM, Samaratunga H, Grant DM, McManus ME . (2000). Toxicol Sci 54: 19–29.

  • Woodhouse KW, Adams PC, Clothier A, Mucklow JC, Rawlins MD . (1982). Hum Toxicol 1: 443–445.

  • Yerokun T, Kirlin WG, Trinidad A, Ferguson RJ, Ogolla F, Andrews AF et al. (1989). Drug Metab Dispos 17: 231–237.

  • Yu MC, Skipper PL, Taghizadeh K, Tannenbaum SR, Chan KK, Henderson BE et al. (1994). J Natl Cancer Inst 86: 712–716.

  • Zang Y, Zhao S, Doll MA, Hein DW . (2005). Proc Amer Assoc Cancer Res 46 (abstract #4060).

  • Zang Y, Zhao S, Doll MA, States JC, Hein DW . (2004). Pharmacogenetics 14: 717–723.

  • Zhang X, Lambert JC, Doll MA, Walraven JM, Arteel GE, Hein DW . (2006). J Pharmacol Exp Ther 316 (in press).

Download references

Acknowledgements

We gratefully acknowledges the assistance of Dr M Garcia-Closas for providing Figure 7 as an update from that recently published in The Lancet (Garcia-Closas et al., 2005). We also thank the faculty, staff and students at the University of Louisville who reviewed and improved the manuscript. Studies and hypotheses from the author's laboratory described in this paper have been supported by over 20 years of research funding from the National Cancer Institute (R01-CA34627) and more recently by Philip Morris USA and the Kentucky Lung Cancer Research Program.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA

    D W Hein

  2. James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA

    D W Hein

Authors
  1. D W Hein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D W Hein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hein, D. N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk. Oncogene 25, 1649–1658 (2006). https://doi.org/10.1038/sj.onc.1209374

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209374

Keywords

This article is cited by

Search

Advanced search

Quick links