Polymorphism in the N-acetyltransferase 1 (NAT1) polyadenylation signal: association of NAT1*10 allele with higher N-acetylation activity in bladder and colon tissue.
Exposures to carcinogens present in the diet, in cigarette smoke, or in the environment have been associated with increased risk of bladder and colorectal cancer. The aromatic amines and their metabolites, a class of carcinogen implicated in these exposures, can be N- or O-acetylated by the NAT1 and NAT2 enzymes. Acetylation may result in activation to DNA-reactive metabolites or, in some cases, detoxification. Many studies have focused on genetic variation in NAT2 and its potential as a risk factor in bladder and colorectal cancer; however, NAT1 activity is higher in bladder and colonic mucosa than NAT2, and the NAT1 enzyme also exhibits phenotypic variation among human tissue samples. We hypothesized that specific genetic variants in the polyadenylation signal of the NAT1 gene would alter tissue levels of NAT1 enzyme activity and used a PCR-based method to distinguish polymorphic NAT1 alleles in samples obtained from 45 individuals. When the NAT1 genotype was compared with the NAT1 phenotype in bladder and colon tissue samples (p-aminobenzoic acid activity), we observed a approximately 2-fold higher NAT1 enzyme activity in samples from individuals who inherited a variant polyadenylation signal (NAT1*10 allele). This is the first observation relating a genetic polymorphism in NAT1 to a rapid/slow NAT1 phenotype in humans.
Bell
D A
DA
Laboratory of Biochemical Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Badawi
A F
AF
Lang
N P
NP
Ilett
K F
KF
Kadlubar
F F
FF
Hirvonen
A
A
D000107:Acetylation; D000483:Alleles; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001483:Base Sequence; D003106:Colon / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D011061:Poly A / Q000378:metabolism*; D011110:Polymorphism, Genetic; D001743:Urinary Bladder / Q000201:enzymology*
D011061:Poly A; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human