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ROLE OF HUMAN ARYLAMINE N-ACETYL TRANSFERASE IN CARCINOGEN METABOLISM AND HUMAN BREAST CANCER PROGRESSION Carmine S. Leggett August 16, 2012 Human arylamine N-acetyltransferase (NAT) is a phase II cytosolic enzyme that occurs as two isozymes, NAT1 and NAT2. This family of polymorphic enzymes catalyzes the detoxification and/or activation of many aromatic and heterocyclic amine drugs and carcinogens. These metabolism reactions can lead to detoxification of xenobiotics by N-acetylation, or bioactivation by O-acetylation which is preceded by cytochrome P450 (CYP) hydroxylation. This study evaluates the role of human arylamine Nacetyltransferase in carcinogen metabolism as it pertains to substrate selectivity, kinetic activity towards arylamine and alkylaniline substrates, and toxicological risk. Here we introduce the use of immortalized human fibroblasts (GM4429) to investigate the effects of combinations of human NAT1, human NAT2 haplotypes (NA T2*4, NA T2*S8, or NAT2*78), and varying CYP1 A2 enzymatic activity on carcinogen metabolism. We determined the apparent Michaelis-Menten constants of human NAT1 and human NAT2 for several well-characterized and

Role of human arylamine N-acetyltransferase in carcinogen metabolism and human breast cancer progression.