Differences between human slow N-acetyltransferase 2 alleles in levels of 4-aminobiphenyl-induced DNA adducts and mutations.
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.
Bendaly
Jean
J
Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, United States.
Doll
Mark A
MA
Millner
Lori M
LM
Metry
Kristin J
KJ
Smith
Ned B
NB
Pierce
William M
WM
Hein
David W
DW
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
D000611:Aminobiphenyl Compounds; D018736:DNA Adducts; C006757:4-biphenylamine; D019363:Cytochrome P-450 CYP1A1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human
Pharmacogenetics. 2000 Jul;10(5):461-9
10898115
Cancer Detect Prev. 2004;28(3):187-93
15225898
Carcinogenesis. 1997 Nov;18(11):2127-32
9395212
Cancer Epidemiol Biomarkers Prev. 2000 Jan;9(1):29-42
10667461
Hepatology. 2002 Apr;35(4):883-9
11915035
Polycycl Aromat Compd. 2008 Aug;28(4-5):402-417
19122802
Mol Cell Biol. 1988 Mar;8(3):1137-46
2835663
Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1503-9
17627018
Lancet. 1982 Oct 16;2(8303):842-5
6126711
Biochem Biophys Res Commun. 1992 Jun 30;185(3):839-44
1627140
Am J Epidemiol. 2000 Aug 1;152(3):226-32
10933269
Pharmacogenetics. 2003 Jul;13(7):399-407
12835615
Cancer Causes Control. 2003 Feb;14(1):43-51
12708724
Xenobiotica. 2009 May;39(5):399-406
19301197
Tuberculosis (Edinb). 2007 Nov;87(6):551-6
17950035
J Biol Chem. 1999 Dec 3;274(49):34519-22
10574910
Chem Res Toxicol. 2009 Apr;22(4):726-33
19243127
Arch Toxicol. 2007 Jan;81(1):19-25
16947004
Cancer Res. 1995 Aug 15;55(16):3531-6
7627960
Carcinogenesis. 2009 Jun;30(6):968-76
19307236
JAMA. 1996 Nov 13;276(18):1494-501
8903261
Cancer Epidemiol Biomarkers Prev. 1998 May;7(5):371-8
9610785
Arch Toxicol. 1994;68(2):129-33
8179482
Chem Res Toxicol. 2006 Sep;19(9):1182-90
16978022
Am J Epidemiol. 2007 Aug 1;166(3):246-54
17535831
Mutat Res. 1997 Aug 1;378(1-2):97-112
9288889
Curr Drug Metab. 2008 Jul;9(6):471-86
18680467
Cancer Detect Prev. 2002;26(1):10-4
12088197
Lancet Oncol. 2008 Apr;9(4):322-3
18405853
Carcinogenesis. 2007 Feb;28(2):342-9
16926175
Somatic Cell Genet. 1980 May;6(3):391-405
7404270
Expert Opin Drug Metab Toxicol. 2009 Apr;5(4):353-66
19379125
Cancer Epidemiol Biomarkers Prev. 1997 Apr;6(4):225-31
9107426
Int J Cancer. 2001 Apr 15;92(2):220-5
11291049
Carcinogenesis. 2003 Apr;24(4):719-25
12727801
Mutat Res. 2002 Sep 30;506-507:65-77
12351146
Cancer Epidemiol Biomarkers Prev. 2008 Jan;17(1):15-26
18187392
J Natl Cancer Inst. 2003 Aug 20;95(16):1227-37
12928348
Arch Biochem Biophys. 2007 Aug 15;464(2):169-75
17601487
Int J Cancer. 1999 Jul 19;82(2):175-9
10389748
J Urol. 1999 May;161(5):1672-5
10210437
Carcinogenesis. 2002 Feb;23(2):301-6
11872636
Carcinogenesis. 2007 Aug;28(8):1665-71
17434923
Cancer Res. 1996 Sep 1;56(17):3915-25
8752158
Curr Drug Metab. 2008 Jul;9(6):538-45
18680474
Oncogene. 2006 Mar 13;25(11):1649-58
16550165
Toxicol Sci. 2009 Nov;112(1):211-20
19692670
Rapid Commun Mass Spectrom. 2003;17(18):2125-32
12955743
Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5350-4
2052611
Mol Carcinog. 2007 Jul;46(7):553-63
17295238
Environ Mol Mutagen. 2002;39(4):306-13
12112382
Breast Cancer Res. 2005;7(3):R385-93
15987434
Annu Rev Pharmacol Toxicol. 2005;45:27-49
15822170
Chem Res Toxicol. 2005 Apr;18(4):692-9
15833029
Eur J Cancer. 1993;29A(8):1199-207
8518034
Int J Cancer. 2006 Oct 15;119(8):1961-9
16721725
Lancet. 2003 Mar 8;361(9360):865-72
12642066
Cancer Epidemiol Biomarkers Prev. 2002 Aug;11(8):698-704
12163321
Ther Drug Monit. 2005 Jun;27(3):297-304
15905799
Proc Natl Acad Sci U S A. 1982 Feb;79(4):1269-72
6951172
Environ Mol Mutagen. 2002;39(2-3):184-92
11921188
Hum Mol Genet. 1994 May;3(5):729-34
8081359
Nat Rev Genet. 2002 May;3(5):391-7
11988764
Int J Cancer. 2005 Apr 20;114(4):579-84
15609332
Carcinogenesis. 1993 Aug;14(8):1633-8
8353847
Toxicol Lett. 2006 Apr 10;162(2-3):246-9
16256281
Toxicol Appl Pharmacol. 1996 Nov;141(1):248-55
8917697
Pharmacogenetics. 2004 Nov;14(11):717-23
15564878