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 |
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Authors: | Jefferson, Felicia A. Xiao, Gong H. Hein, David W. |
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Affiliation: | * 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. |
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Abstract: | Aromatic and heterocyclic amine carcinogens present in the dietand in cigarette smoke induce breast tumors in rats. N-acetyltransferase1 (NAT1) and N-acetyltransferase 2 (NAT2) enzymes have importantroles in their metabolic activation and deactivation. Humanepidemiological studies suggest that genetic polymorphisms inNAT1 and/or NAT2 modify breast cancer risk in women exposedto these carcinogens. p-Aminobenzoic acid (selective for ratNAT2) and sulfamethazine (SMZ; selective for rat NAT1) N-acetyltransferasecatalytic activities were both expressed in primary culturesof rat mammary epithelial cells. PABA, 2-aminofluorene, and4-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]quinoxalineO-acetyltransferase activities were two- to threefold higherin mammary epithelial cell cultures from rapid than slow acetylatorrats. In contrast, SMZ (a rat NAT1-selective substrate) N-acetyltransferaseactivity did not differ between rapid and slow acetylators.Rat mammary cells cultured in the medium supplemented 24 h with10µM ABP showed downregulation in the N-and O-acetylationof all substrates tested except for the NAT1-selective substrateSMZ. This downregulation was comparable in rapid and slow NAT2acetylators. These studies clearly show NAT2 acetylator genotype–dependentN- and O-acetylation of aromatic and heterocyclic amine carcinogensin rat mammary epithelial cell cultures to be subject to downregulationby the arylamine carcinogen ABP. |
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Keywords: | N-acetyltransferase 1 N-acetyltransferase 2 4-aminobiphenyl mammary epithelial cells downregulation heterocyclic amines. |
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