ToxSci Advance Access published online on October 8, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn216
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4-Aminobiphenyl down regulation of NAT2 acetylator genotype-dependent N- and O-acetylation of aromatic and heterocyclic amine carcinogens in primary mammary epithelial cell cultures from rapid and slow acetylator rats
Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky 40292
3 To whom correspondence should be addressed at Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, Phone: (502) 852-5141; Fax: (502) 852-7868; Email: d.hein{at}louisville.edu
Received September 9, 2008; revision received October 1, 2008; accepted October 2, 2008
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Abstract |
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Aromatic and heterocyclic amine carcinogens present in the diet and in cigarette smoke induce breast tumors in rats. N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) enzymes have important roles in their metabolic activation and deactivation. Human epidemiological studies suggest that genetic polymorphisms in NAT1 and/or NAT2 modify breast cancer risk in women exposed to these carcinogens. p-Aminobenzoic acid (PABA; selective for rat NAT2) and sulfamethazine (SMZ; selective for rat NAT1) N-acetyltransferase catalytic activities were both expressed in primary cultures of rat mammary epithelial cells. PABA , 2-aminofluorene (AF) and 4-aminobiphenyl (ABP) N-acetyltransferase and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (N-OH-PhIP) and N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline] (N-OH-MeIQx) O-acetyltransferase activities were two to three-fold higher in mammary epithelial cell cultures from rapid than slow acetylator rats. In contrast, SMZ (a rat NAT1-selective substrate) N-acetyltransferase activity did not differ between rapid and slow acetylators. Rat mammary cells cultured in the medium supplemented 24 hr with 10 µM ABP showed down regulation in the N-and O-acetylation of all substrates tested except for the NAT1 selective substrate SMZ. This down regulation was comparable in rapid and slow NAT2 acetylators. These studies clearly show NAT2 acetylator genotype dependent N- and O- acetylation of aromatic and heterocyclic amine carcinogens in rat mammary epithelial cell cultures to be subject to down regulation by the arylamine carcinogen 4-aminobiphenyl.
Key Words: N-acetyltransferase 1; N-acetyltransferase 2; 4-aminobiphenyl; mammary epithelial cells; down regulation; heterocyclic amines.
1 Current address: Morehouse School of Medicine, Atlanta, Georgia USA, email: fjefferson{at}msm.edu
2 Current address: Health Canada, Ottawa, Ontario Canada, email: Gong-hua_Xiao{at}hc-sc.gc.ca