title: Differences between human slow N-acetyltransferase 2 alleles in levels of 4-aminobiphenyl-induced DNA adducts and mutations.
abstract: Aromatic amines such as 4-aminobiphenyl (ABP) require biotransformation to exert their carcinogenic effects. Genetic polymorphisms in biotransformation enzymes such as N-acetyltransferase 2 (NAT2) may modify cancer risk following exposure. Nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells stably transfected with human cytochrome P4501A1 (CYP1A1) and a single copy of either NAT2*4 (rapid acetylator), NAT2*5B (common Caucasian slow acetylator), or NAT2*7B (common Asian slow acetylator) alleles (haplotypes) were treated with ABP to test the effect of NAT2 polymorphisms on DNA adduct formation and mutagenesis. ABP N-acetyltransferase catalytic activities were detectable only in cell lines transfected with NAT2 and were highest in cells transfected with NAT2*4, lower in cells transfected with NAT2*7B, and lowest in cells transfected with NAT2*5B. Following ABP treatment, N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP) was the primary adduct formed. Cells transfected with both CYP1A1 and NAT2*4 showed the highest concentration-dependent cytotoxicity, hypoxanthine phosphoribosyl transferase (hprt) mutants, and dG-C8-ABP adducts. Cells transfected with CYP1A1 and NAT2*7B showed lower levels of cytotoxicity, hprt mutagenesis, and dG-C8-ABP adducts. Cells transfected with CYP1A1 only or cells transfected with both CYP1A1 and NAT2*5B did not induce cytotoxicity, hprt mutagenesis or dG-C8-ABP adducts. ABP-DNA adduct levels correlated very highly (r>0.96) with ABP-induced hprt mutant levels following each treatment. The results of the present study suggest that investigations of NAT2 genotype or phenotype associations with disease or toxicity could be more precise and reproducible if heterogeneity within the "slow" NAT2 acetylator phenotype is considered and incorporated into the study design.
authors.affiliation: Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, United States.
authors.forename: Jean
authors.initials: J
authors.lastname: Bendaly
authors.forename: Mark A
authors.initials: MA
authors.lastname: Doll
authors.forename: Lori M
authors.initials: LM
authors.lastname: Millner
authors.forename: Kristin J
authors.initials: KJ
authors.lastname: Metry
authors.forename: Ned B
authors.initials: NB
authors.lastname: Smith
authors.forename: William M
authors.initials: WM
authors.lastname: Pierce
authors.forename: David W
authors.initials: DW
authors.lastname: Hein
mesh_terms: D000483:Alleles; D000611:Aminobiphenyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D018736:DNA Adducts; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000611:Aminobiphenyl Compounds; D018736:DNA Adducts; C006757:4-biphenylamine; D019363:Cytochrome P-450 CYP1A1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human
references.citation: Pharmacogenetics. 2000 Jul;10(5):461-9
references.pmid: 10898115
references.citation: Cancer Detect Prev. 2004;28(3):187-93
references.pmid: 15225898
references.citation: Carcinogenesis. 1997 Nov;18(11):2127-32
references.pmid: 9395212
references.citation: Cancer Epidemiol Biomarkers Prev. 2000 Jan;9(1):29-42
references.pmid: 10667461
references.citation: Hepatology. 2002 Apr;35(4):883-9
references.pmid: 11915035
references.citation: Polycycl Aromat Compd. 2008 Aug;28(4-5):402-417
references.pmid: 19122802
references.citation: Mol Cell Biol. 1988 Mar;8(3):1137-46
references.pmid: 2835663
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1503-9
references.pmid: 17627018
references.citation: Lancet. 1982 Oct 16;2(8303):842-5
references.pmid: 6126711
references.citation: Biochem Biophys Res Commun. 1992 Jun 30;185(3):839-44
references.pmid: 1627140
references.citation: Am J Epidemiol. 2000 Aug 1;152(3):226-32
references.pmid: 10933269
references.citation: Pharmacogenetics. 2003 Jul;13(7):399-407
references.pmid: 12835615
references.citation: Cancer Causes Control. 2003 Feb;14(1):43-51
references.pmid: 12708724
references.citation: Xenobiotica. 2009 May;39(5):399-406
references.pmid: 19301197
references.citation: Tuberculosis (Edinb). 2007 Nov;87(6):551-6
references.pmid: 17950035
references.citation: J Biol Chem. 1999 Dec 3;274(49):34519-22
references.pmid: 10574910
references.citation: Chem Res Toxicol. 2009 Apr;22(4):726-33
references.pmid: 19243127
references.citation: Arch Toxicol. 2007 Jan;81(1):19-25
references.pmid: 16947004
references.citation: Cancer Res. 1995 Aug 15;55(16):3531-6
references.pmid: 7627960
references.citation: Carcinogenesis. 2009 Jun;30(6):968-76
references.pmid: 19307236
references.citation: JAMA. 1996 Nov 13;276(18):1494-501
references.pmid: 8903261
references.citation: Cancer Epidemiol Biomarkers Prev. 1998 May;7(5):371-8
references.pmid: 9610785
references.citation: Arch Toxicol. 1994;68(2):129-33
references.pmid: 8179482
references.citation: Chem Res Toxicol. 2006 Sep;19(9):1182-90
references.pmid: 16978022
references.citation: Am J Epidemiol. 2007 Aug 1;166(3):246-54
references.pmid: 17535831
references.citation: Mutat Res. 1997 Aug 1;378(1-2):97-112
references.pmid: 9288889
references.citation: Curr Drug Metab. 2008 Jul;9(6):471-86
references.pmid: 18680467
references.citation: Cancer Detect Prev. 2002;26(1):10-4
references.pmid: 12088197
references.citation: Lancet Oncol. 2008 Apr;9(4):322-3
references.pmid: 18405853
references.citation: Carcinogenesis. 2007 Feb;28(2):342-9
references.pmid: 16926175
references.citation: Somatic Cell Genet. 1980 May;6(3):391-405
references.pmid: 7404270
references.citation: Expert Opin Drug Metab Toxicol. 2009 Apr;5(4):353-66
references.pmid: 19379125
references.citation: Cancer Epidemiol Biomarkers Prev. 1997 Apr;6(4):225-31
references.pmid: 9107426
references.citation: Int J Cancer. 2001 Apr 15;92(2):220-5
references.pmid: 11291049
references.citation: Carcinogenesis. 2003 Apr;24(4):719-25
references.pmid: 12727801
references.citation: Mutat Res. 2002 Sep 30;506-507:65-77
references.pmid: 12351146
references.citation: Cancer Epidemiol Biomarkers Prev. 2008 Jan;17(1):15-26
references.pmid: 18187392
references.citation: J Natl Cancer Inst. 2003 Aug 20;95(16):1227-37
references.pmid: 12928348
references.citation: Arch Biochem Biophys. 2007 Aug 15;464(2):169-75
references.pmid: 17601487
references.citation: Int J Cancer. 1999 Jul 19;82(2):175-9
references.pmid: 10389748
references.citation: J Urol. 1999 May;161(5):1672-5
references.pmid: 10210437
references.citation: Carcinogenesis. 2002 Feb;23(2):301-6
references.pmid: 11872636
references.citation: Carcinogenesis. 2007 Aug;28(8):1665-71
references.pmid: 17434923
references.citation: Cancer Res. 1996 Sep 1;56(17):3915-25
references.pmid: 8752158
references.citation: Curr Drug Metab. 2008 Jul;9(6):538-45
references.pmid: 18680474
references.citation: Oncogene. 2006 Mar 13;25(11):1649-58
references.pmid: 16550165
references.citation: Toxicol Sci. 2009 Nov;112(1):211-20
references.pmid: 19692670
references.citation: Rapid Commun Mass Spectrom. 2003;17(18):2125-32
references.pmid: 12955743
references.citation: Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5350-4
references.pmid: 2052611
references.citation: Mol Carcinog. 2007 Jul;46(7):553-63
references.pmid: 17295238
references.citation: Environ Mol Mutagen. 2002;39(4):306-13
references.pmid: 12112382
references.citation: Breast Cancer Res. 2005;7(3):R385-93
references.pmid: 15987434
references.citation: Annu Rev Pharmacol Toxicol. 2005;45:27-49
references.pmid: 15822170
references.citation: Chem Res Toxicol. 2005 Apr;18(4):692-9
references.pmid: 15833029
references.citation: Eur J Cancer. 1993;29A(8):1199-207
references.pmid: 8518034
references.citation: Int J Cancer. 2006 Oct 15;119(8):1961-9
references.pmid: 16721725
references.citation: Lancet. 2003 Mar 8;361(9360):865-72
references.pmid: 12642066
references.citation: Cancer Epidemiol Biomarkers Prev. 2002 Aug;11(8):698-704
references.pmid: 12163321
references.citation: Ther Drug Monit. 2005 Jun;27(3):297-304
references.pmid: 15905799
references.citation: Proc Natl Acad Sci U S A. 1982 Feb;79(4):1269-72
references.pmid: 6951172
references.citation: Environ Mol Mutagen. 2002;39(2-3):184-92
references.pmid: 11921188
references.citation: Hum Mol Genet. 1994 May;3(5):729-34
references.pmid: 8081359
references.citation: Nat Rev Genet. 2002 May;3(5):391-7
references.pmid: 11988764
references.citation: Int J Cancer. 2005 Apr 20;114(4):579-84
references.pmid: 15609332
references.citation: Carcinogenesis. 1993 Aug;14(8):1633-8
references.pmid: 8353847
references.citation: Toxicol Lett. 2006 Apr 10;162(2-3):246-9
references.pmid: 16256281
references.citation: Toxicol Appl Pharmacol. 1996 Nov;141(1):248-55
references.pmid: 8917697
references.citation: Pharmacogenetics. 2004 Nov;14(11):717-23
references.pmid: 15564878