N-Acetyltransferase 1 Polymorphism and Breast Cancer Risk

摘要

activation or inactivation. NAT1*10 and NAT1*14, common variant alleles have been associated with increased risk for numerous cancers including breast. NAT1 is also upregulated in breast cancer. We employed a novel approach to study functional differences caused by NAT1*10 and NAT1*14 polymorphisms by using constructs that mimic complete human mRNAs by including the 5 -UTR, coding region and 3 -UTR. Significantly more enzymatic activity, protein expression, mRNA levels and 4-aminobiphenyl-induced DNA adducts and mutants were observed in all constructs containing the NATb 5 -UTR compared to those containing the NATa 5 -UTR. After treatment with 4-aminobiphenyl(ABP), more DNA adducts and mutagenesis was observed in cells transfected with NATb constructs than cells transfected with NATa constructs. Kinetic parameters for NAT1*14B compared to NAT1*4 were determined. The NAT1*14B v(max) for PABA, ABP, and N-OH- ABP was less than NAT1*4 vmax. The NAT1*14B v(max)/km, or instrinsic clearance, was lower for PABA when compared to NAT1*4 v(max)/km. The NAT1*14B v(max)/km was not different compared to NAT1*4 v(max)/km for ABP, but the NAT1*14B v(max)/km was higher for N -OH-ABP compared to vmax/km NAT1*4 . This indicates that clearance for the NAT1 variant, NAT1*14B, is substrate dependent. Consequently, cancer risk related to NAT1*14B is likely also substrate dependent. NATb/NAT1*10 and NATb/NAT1*10B transiently and stably transfected cells resulted in higher mRNA levels, protein expression, ABP induced cytotoxicity and hprt -mutants. This indicates that individuals possessing a NAT1*10 or NAT1*10B genotype are associated with an increased cancer risk than individuals who possess a NAT1*4 genotype.