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Human acetylator genotype: Relationship to colorectal cancer incidence and arylamine N-acetyltransferase expression in colon cytosol

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Abstract

Polymorphic expression of arylamine N-acetyltransferase (EC 2.3.1.5) may be a differential risk factor in metabolic activation of arylamine carcinogens and susceptibility to cancers related to arylamine exposures. Human epidemiological studies suggest that rapid acetylator phenotype may be associated with higher incidences of colorectal cancer. We used restriction fragment length polymorphism analysis to determine acetylator genotypes of 44 subjects with colorectal cancer and 28 non-cancer subjects of similar ethnic background (i.e., approximately 25% Black and 75% White). The polymorphic N-acetyltransferase gene (NAT2) was amplified by the polymerase chain reaction from DNA templates derived from human colons of colorectal and non-cancer subjects. No significant differences inNAT2 allelic frequencies (i.e., WT, M1, M2, M3 alleles) or in acetylator genotypes were found between the colorectal cancer and non-cancer groups. No significant differences inNAT2 allelic frequencies were observed between Whites and Blacks or between males and females. Cytosolic preparations from the human colons were tested for expression of arylamine N-acetyltransferase activity. Although N-acetyltransferase activity was expressed for each of the arylamines tested (i.e., p-aminobenzoic acid, 4-aminobiphenyl, 2-aminofluorene, β-naphthylamine), no correlation was observed between acetylator genotype and expression of human colon arylamine N-acetyltransferase activity. Similarly, no correlation was observed between subject age and expression of human colon arylamine N-acetyltransferase activity. These results suggest that arylamine N-acetyltransferase activity expressed in human colon is catalyzed predominantly by NAT1, an arylamine N-acetyltransferase that is not regulated byNAT2 acetylator genotype. The ability to determine acetylator genotype from DNA derived from human surgical samples should facilitate further epidemiological studies to assess the role of acetylator genotype in various cancers.

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References

  • Allgayer H, Ahnfelt NO, Kruis W, Klotz U, Frank-Holmberg K, Soderberg HB, Paumgartner G (1989) Colonic N-acetylation of 5-aminosalicylic acid in inflammatory bowel disease. Gastroenterology 97: 38–41

    PubMed  Google Scholar 

  • Baird MB, Birnbaum LS (1979) Increased production of mutagenic metabolites of carcinogens by tissues from senescent rodents. Cancer Res 39: 4752–4755

    PubMed  Google Scholar 

  • Birnbaum LS (1987) Age related changes in carcinogen metabolism. J Am Geriat Soc 35: 51–60

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Blum M, Demierre A, Grant DM, Heim M, Meyer UA (1991) Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc Natl Acad Sci USA 88: 5237–5241

    PubMed  Google Scholar 

  • Bock CW (1992) Metabolic polymorphisms affecting activation of toxic and mutagenic arylamines. TIPS 13: 223–226

    PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Chem 72: 248–254

    Google Scholar 

  • Caporaso N, Landi MT, Vineis P (1991) Relevance of metabolic polymorphisms to human carcinogenesis: evaluation of epidemiologic evidence. Pharmacogenetics 1: 4–19

    PubMed  Google Scholar 

  • Cartwright RA, Glashan RW, Rogers HJ, Ahmad RA, Hall DB, Higgins E, Kahn MA (1982) Role of N-acetyltransferase phenotypes in bladder carcinogenesis: a pharmacogenetic epidemiological approach to bladder cancer. Lancet 2: 842–846

    PubMed  Google Scholar 

  • Cribb AE, Grant DM, Miller MA, Spielberg SP (1991) Expression of monomorphic arylamine N-acetyltransferase (NAT1) in human leukocytes. J Pharmacol Exp Ther 259: 1241–1246

    PubMed  Google Scholar 

  • Deguchi T (1992) Sequences and expression of alleles of polymorphic arylamine N-acetyltransferase of human liver. J Biol Chem 267: 18140–18147

    PubMed  Google Scholar 

  • Evans DAP (1989) N-acetyltransferase. Pharmacol Ther 42: 157–234

    PubMed  Google Scholar 

  • Evans DAP, Manley KA, McKusick VA (1960) Genetic control of isoniazid metabolism in man. BMJ ii: 485–491

    Google Scholar 

  • Farah F, Taylor W, Rawlins MD, James O (1977) Hepatic drug acetylation and oxidation: effects of aging in man. BMJ ii: 155–156

    Google Scholar 

  • Fearon ER, Jones PA (1992) Progressing toward a molecular description of colorectal cancer development. FASEB J 6: 2783–2790

    PubMed  Google Scholar 

  • Fettman MJ, Butler RN, McMichael AJ, Roberts-Thomson IC (1991) Metabolic phenotypes and colorectal cancer. J Gastroenterol Hepat 6: 81–89

    Google Scholar 

  • Flammang TJ, Yamazoe Y, Guengerich FP, Kadlubar FF (1987) The S-acetyl coenzyme A-dependent metabolic activation of the carcinogen N-hydroxy-2-aminofluorene by human liver cytosol and its relationship to the aromatic amine N-acetyltransferase phenotype. Carcinogenesis 8: 1967–1970

    PubMed  Google Scholar 

  • Flammang TJ, Hein DW, Talaska G, Kadlubar FF (1988) N-Hydroxyarylamine O-acetyltransferase and its relationship to aromatic amine N-acetyltransferase polymorphism in the inbred hamster and in human tissue cytosol. In: King CM, Romano LJ, Schuetzle D (eds) Mutagenic responses to aromatic amines and nitroarenes. Elsevier Science Publishing, New York, pp 137–148

    Google Scholar 

  • Gachályi B, Vas Á, Hajós P, Káldor A (1984) Acetylator phenotypes: effect of age. Eur J Clin Pharmacol 26: 43–45

    PubMed  Google Scholar 

  • Glowinski IB, Radtke HE, Weber WW (1978) Genetic variation in the N-acetylation of carcinogenic arylamines by human and rabbit liver. Mol Pharmacol 14: 940–949

    PubMed  Google Scholar 

  • Grant DM, Blum M, Beer M, Meyer UA (1991) Monomorphic and polymorphic human arylamine N-acetyltransferases: a comparison of liver isozymes and expressed products of two cloned genes. Mol Pharmacol 39: 184–191

    PubMed  Google Scholar 

  • Harris CC (1991) Chemical and physical carcinogenesis: advances and perspectives for the 1990s. Cancer Res (Suppl) 51: 5023s-5044s

    Google Scholar 

  • Hein DW (1988) Acetylator genotype and arylamine-induced carcinogenesis. Biochim Biophys Acta 948: 37–66

    PubMed  Google Scholar 

  • Hein DW, Kirlin WG, Yerokun T, Trinidad A, Ogolla F (1987) Inheritance of acetylator genotype-dependent arylamine N-acetyltransferase in hamster bladder cytosol. Carcinogenesis 8: 647–652

    PubMed  Google Scholar 

  • Hein DW, Rustan TD, Bucher KD, Furman EJ, Martin WJ (1991a) Extrahepatic expression of the N-acetylation polymorphism toward arylamine carcinogens in tumor target organs of an inbred rat model. J Pharmacol Exp Ther 258: 232–236

    PubMed  Google Scholar 

  • Hein DW, Rustan TD, Bucher KD, Miller LS (1991b), Polymorphic and monomorphic expression of arylamine carcinogen N-acetyltransferase isozymes in tumor target organ cytosols of Syrian hamsters congenic at the polymorphic acetyltransferase locus. J Pharmacol Exp Ther 259: 699–704

    PubMed  Google Scholar 

  • Hein DW, Doll MA, Rustan TD, Gray K, Feng Y, Ferguson RJ, Grant DM (1993b) Metabolic activation and deactivation of arylamine carcinogens by recombinant human NAT1 and polymorphic NAT2 acetyltransferases. Carcinogenesis (in press)

  • Hein DW, Doll MA, Gray K, Rustan TD, Ferguson RJ (1993 a) Metabolic activation of N-hydroxy-2-aminofluorene and N-hydroxy-2-acetylaminofluorene by monomorphic N-acetyltransferase (NAT1) and polymorphic N-acetyltransferase (NAT2) in colon cytosols of Syrian hamsters congenic at the NAT2 locus. Cancer Res 53: 509–514

    PubMed  Google Scholar 

  • Hickman D, Sim E (1991) N-acetyltransferase polymorphism: comparison of phenotype and genotype in humans. Biochem Pharmacol 42: 1007–1014

    PubMed  Google Scholar 

  • Ilett KF, David BM, Detchon P, Castleden WM, Kwa R (1987) Acetylation phenotype in colorectal carcinoma. Cancer Res 47: 1466–1469

    PubMed  Google Scholar 

  • Ilett KF, Reeves PT, Minchin RF, Kinnear BF, Watson HF, Kadlubar FF (1991) Distribution of acetyltransferase activities in the intestines of rapid and slow acetylator rabbits. Carcinogenesis 12: 1465–1469

    PubMed  Google Scholar 

  • Iselius L, Evans DAP (1983) Formal genetics of isoniazid metabolism in man. Clin Pharmacokinet 8: 541–544

    PubMed  Google Scholar 

  • Kergueris MF, Bourin M, Larousse C (1986) Pharmacokinetics of isoniazid: influence of age. Eur J Clin Pharmacol 30: 335–340

    PubMed  Google Scholar 

  • Kirlin WG, Trinidad A, Yerokun T, Ogolla F, Ferguson RJ, Andrews AF, Brady PK, Hein DW (1989) Polymorphic expression of AcCoAdependent arylamine N-acetyltransferase and AcCoA-dependent O-acetyltransferase-mediated activation of N-hydroxyarylamines by human bladder cytosol. Cancer Res 49: 2448–2454

    PubMed  Google Scholar 

  • Kirlin WG, Ogolla F, Andrews AF, Trinidad A, Ferguson RJ, Yerokun T, Mpezo M, Hein DW (1991) Acetylator genotype-dependent expression of arylamine N-acetyltransferase in human colon cytosol from non-cancer and colorectal cancer patients. Cancer Res 51: 549–555

    PubMed  Google Scholar 

  • Ladero JM, Gonzalez JF, Benitez J, Vargas E, Fernandez MJ, Baki W, Diaz-Rubio M (1991) Acetylator polymorphism in human colorectal carcinoma. Cancer Res 51: 2098–2100

    PubMed  Google Scholar 

  • Lang NP, Chu DZJ, Hunter CF, Kendall DC, Flammang TJ, Kadlubar FF (1986) Role of aromatic amine acetyltransferase in colorectal cancer. Arch Surg 121: 1259–1261

    PubMed  Google Scholar 

  • Lindsay RM, Baty JD (1988) Inter-individual variation of human blood N-acetyltransferase activity in vitro. Biochem Pharmacol 37: 3915–3921

    PubMed  Google Scholar 

  • Lower GM, Nilsson T, Nelson CE, Wolf H, Gamsky TE, Bryan GT (1979) N-acetyltransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Preliminary results in Sweden and Denmark. Environ Health Perspec 29: 71–79

    Google Scholar 

  • Minchin RF, Reeves PT, Teitel CH, McManus ME, Mojarrabi B, Ilett KF, Kadlubar FF (1992) N- and O-acetylation of aromatic and heterocyclic amine carcinogens by human monomorphic and polymorphic acetyltransferases expressed inCOS-1 cells. Biochem Biophys Res Commun 185: 839–844

    PubMed  Google Scholar 

  • Nebert DW (1991) Role of genetics and metabolism in human cancer risk. Mutat Res 247: 267–281

    PubMed  Google Scholar 

  • Nomura A (1990) An international search for the causative factors of colorectal cancer. J Natl Cancer Inst 82: 894–895

    PubMed  Google Scholar 

  • Ogolla F, Ferguson RJ, Kirlin WG, Trinidad A, Andrews AF, Mpezo M, Hein DW (1990) Acetylator genotype-dependent expression of arylamine N-acetyltransferase and N-hydroxyarylamine O-acetyltransferase in Syrian inbred hamster intestine and colon: identity with the hepatic acetylation polymorphism. Drug Metab Dispos 18: 680–685

    PubMed  Google Scholar 

  • Ohsako S, Deguchi T (1990) Cloning and expression of cDNAs for polymorphic and monomorphic arylamine N-acetyltransferases from human liver. J Biol Chem 265: 4630–4634

    PubMed  Google Scholar 

  • Paulsen O, Nilsson LG (1985) Distribution of acetylator phenotype in relation to age and sex in Swedish patients. Eur J Clin Pharmacol 28: 311–315

    PubMed  Google Scholar 

  • Pink JC, Messing EM, Reznikoff CA, Bryan GT, Swaminathan S (1992) Correlation between N-acetyltransferase activities in uroepithelia and in vivo acetylator phenotype. Drug Metab Dispos 20: 559–565

    PubMed  Google Scholar 

  • Reeves PT, Kinnear BF, Minchin RF, Ilett KF (1992) Distribution of polymorphic N-acetyltransferase in the intestines of rapid acetylator rabbits. Asia Pac J Pharmacol 7: 219–223

    Google Scholar 

  • Roots I, Drakoulis N, Brockmoller J, Janicke I, Cuprunov M, Ritter J (1989) Hydroxylation and acetylation phenotypes as genetic risk factors in certain malignancies. In: Kato R, Estabrook RW, Cayen MN (eds) Xenobiotic metabolism and disposition. Taylor and Francis, London, pp 499–506

    Google Scholar 

  • Turesky RJ, Lang NP, Butler MA, Teitel C, Kadlubar FF (1991) Metabolic activation of carcinogenic heterocyclic aromatic amines by human liver and colon. Carcinogenesis 12: 1839–1845

    PubMed  Google Scholar 

  • Vatsis KP, Martell KJ, Weber WW (1991) Diverse point mutations in the human gene for polymorphic N-acetyltransferase. Proc Natl Acad Sci USA 88: 6333–6337

    PubMed  Google Scholar 

  • Ward A, Hickman D, Gordon JW, Sim E (1992) Arylamine N-acetyltransferase in human red blood cells. Biochem Pharmacol 44: 1099–1104

    PubMed  Google Scholar 

  • Weber WW, Hein DW (1979) Clinical pharmacokinetics of isoniazid. Clin Pharmacokinet 4: 401–422

    PubMed  Google Scholar 

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

    Google Scholar 

  • Weisburger JH (1991) Causes, relevant mechanisms, and prevention of large bowel cancer. Semin Oncol 18: 316–336

    PubMed  Google Scholar 

  • Wohlleb JC, Hunter CF, Blass B, Kadlubar FF, Chu DZJ, Lang NP (1990) Aromatic amine acetyltransferase as a marker for colorectal cancer: environmental and demographic associations. Int J Cancer 46: 22–30

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Morehouse School of Medicine, 30310, Atlanta, GA, USA

    Jose W. Rodriguez, Ward G. Kirlin, Ronald J. Ferguson, Mark E. Lee, Katherine Kemp & David W. Hein

  2. Department of Pharmacology and Toxicology, University of North Dakota School of Medicine, 501 North Columbia Road, 58202-9037, Grand Forks, ND, USA

    Ronald J. Ferguson, Mark A. Doll, Kevin Gray, Timothy D. Rustan & David W. Hein

  3. Department of Microbiology and Immunology, Morehouse School of Medicine, 30310, Atlanta, GA, USA

    Paul Urso

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  1. Jose W. Rodriguez
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  2. Ward G. Kirlin
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  10. David W. Hein
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Rodriguez, J.W., Kirlin, W.G., Ferguson, R.J. et al. Human acetylator genotype: Relationship to colorectal cancer incidence and arylamine N-acetyltransferase expression in colon cytosol. Arch Toxicol 67, 445–452 (1993). https://doi.org/10.1007/BF01969914

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  • DOI: https://doi.org/10.1007/BF01969914

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