Functional expression of human arylamine N-acetyltransferase NAT1*10 and NAT1*11 alleles: a mini review

Abstract

The arylamine N-acetyltransferase (NAT) nomenclature committee assigns functional phenotypes for human arylamine N-acetyltransferase 1 (NAT1) alleles in those instances in which the committee determined a consensus has been achieved in the scientific literature. In the most recent nomenclature update, the committee announced that functional phenotypes for NAT1*10 and NAT1*11 alleles were not provided owing to a lack of consensus. Phenotypic inconsistencies observed among various studies for NAT1*10 and NAT1*11 may be owing to variable allelic expression among different tissues, the limitations of the genotyping assays (which mostly relied on techniques not involving direct DNA sequencing), the differences in recombinant protein expression systems used (bacteria, yeast, and mammalian cell lines) and/or the known inherent instability of human NAT1 protein, which requires very careful handling of native and recombinant cell lysates. Three recent studies provide consistent evidence of the mechanistic basis underlying the functional phenotype of NAT1*10 and NAT1*11 as 'increased-activity' alleles. Some NAT1 variants (e.g. NAT1*14, NAT1*17, and NAT1*22) may be designated as 'decreased-activity' alleles and other NAT1 variants (e.g. NAT1*15 and NAT1*19) may be designated as 'no-activity' alleles compared with the NAT1*4 reference allele. We propose that phenotypic designations as 'rapid' and 'slow' acetylator should be discontinued for NAT1 alleles, although these designations remain very appropriate for NAT2 alleles.

Figure 1:

Overview of NAT1 gene structure and main alternative transcripts. The gene comprises 8 non-coding exons differentially spliced to generate alternative transcripts with variable 5’-UTRs. Exon 9 contains the entire open reading frame (ORF) of the gene, as well as the adjacent 3’-UTR terminated after three differentially utilized polyadenylation signals located at 213 (polyA-1), 331 (polyA-2; major) and 734 (polyA-3) nucleotides downstream of the coding exon. Type I transcripts (A,B) are initiated by promoter NATa located upstream of non-coding exon 1. Type II transcripts (A-D) are initiated by promoter NATb (major) located upstream of non-coding exon 4. The size of introns (in kilobases) is indicated below the gene. The figure was compiled from information previously published [–9, 12] (figure not drawn to scale).