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Pharmacogenetics. 1998 Feb;8(1):67-72.

Functional polymorphism of the human arylamine N-acetyltransferase type 1 gene caused by C190T and G560A mutations.

Author information

1
Department of Pharmacology, University of Western Australia, Nedlands, Australia. nbutcher@receptor.pharm.uwa.edu.au

Abstract

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.

PMID:
9511183
[Indexed for MEDLINE]

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