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

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.