ToxSci Advance Access originally published online on October 8, 2008
Toxicological Sciences 2009 107(1):293-297; doi:10.1093/toxsci/kfn216
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
4-Aminobiphenyl Downregulation 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
,3
* Department of Pharmacology and Toxicology
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky 40292
3 To whom correspondence should be addressed. Fax: (502) 852-7868. E-mail: d.hein{at}louisville.edu.
Received September 9, 2008; accepted October 2, 2008
 |
Abstract |
|---|
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 (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, and 4-aminobiphenyl N-acetyltransferase and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine and N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline O-acetyltransferase activities were two- to threefold 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 h with 10µM ABP showed downregulation in the N-and O-acetylation of all substrates tested except for the NAT1-selective substrate SMZ. This downregulation 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 downregulation by the arylamine carcinogen ABP.
Key Words: N-acetyltransferase 1; N-acetyltransferase 2; 4-aminobiphenyl; mammary epithelial cells; downregulation; heterocyclic amines.
1 Present address: Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310.
2 Present address: Environmental Health Centre, Health Canada, Ottawa, Ontario, Canada K1A 0K9.