N-acetyltransferase 2 acetylator genotype-dependent N-acetylation and toxicity of the arylamine carcinogen β-naphthylamine in cryopreserved human hepatocytes.

Abstract

We used cryopreserved human hepatocytes that express rapid, intermediate, and slow acetylator N-acetyltransferase 2 (NAT2) genotypes to measure the N-acetylation of β-naphthylamine (BNA) which is one of the aromatic amines found in cigarette smoke including E-cigarettes. We investigated the role of NAT2 genetic polymorphism in genotoxicity and oxidative stress induced by BNA. In vitro BNA NAT2 activities in rapid acetylators was 1.6 and 3.5-fold higher than intermediate (p < 0.01) and slow acetylators (p < 0.0001). BNA N-acetylation in situ was 3 to 4- fold higher in rapid acetylators than slow acetylators, following incubation with 10 and 100µM BNA (p < 0.01). DNA damage was two to threefold higher in the rapid versus slow acetylators (p < 0.0001) and 2.5-fold higher in intermediate versus slow acetylators following BNA treatment at 100 and 1000μM, ROS/RNS level was the highest in rapid acetylators followed by intermediate and then slow acetylators (p < 0.0001). Our findings show that theN-acetylation of BNA is NAT2 genotype dependent in cryopreserved human hepatocytes and our data further document an important role for NAT2 genetic polymorphism in modifying BNA-induced genotoxicity and oxidative damage.