Functional polymorphism of the human arylamine N-acetyltransferase type 1 gene caused by C190T and G560A mutations.
Human N-acetyltransferase type 1 (NAT1) catalyses the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is able to bioactivate several known carcinogens. Despite wide inter-individual variability in activity, historically, NAT1 was considered to be monomorphic in nature. However, recent reports of allelic variation at the NAT1 locus suggest that it may be a polymorphically expressed enzyme. In the present study, peripheral blood mononuclear cell NAT1 activity in 85 individuals was found to be bimodally distributed with approximately 8% of the population being slow acetylators. Subsequent sequencing of the individuals having slow acetylator status showed all to have either a C190T or G560A base substitution located in the protein encoding region of the NAT1 gene. The C190T base substitution changed a highly conserved Arg64, which others have shown to be essential for fully functional NAT1 protein. The C190T mutation has not been reported previously and we have named it NAT1 x 17. The G560A mutation is associated with the base substitutions previously observed in the NAT1 x 10 allele and this variant (NAT1 x 14) encodes for a protein with reduced acetylation capacity. A novel method using linear PCR and dideoxy terminators was developed for the detection of NAT1 x 14 and NAT1 x 17. Neither of these variants was found in the rapid acetylator population. We conclude that both the C190T (NAT1 x 17) and G560A (NAT1 x 14) NAT1 structural variants are involved in a distinct NAT1 polymorphism. Because NAT1 can bioactivate several carcinogens, this polymorphism may have implications for cancer risk in individual subjects.
Butcher
N J
NJ
Department of Pharmacology, University of Western Australia, Nedlands, Australia. nbutcher@receptor.pharm.uwa.edu.au
Ilett
K F
KF
Minchin
R F
RF
D010129:4-Aminobenzoic Acid / Q000378:metabolism; D000107:Acetylation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
D017931:DNA Primers; D001191:Arylamine N-Acetyltransferase; D010129:4-Aminobenzoic Acid