Arylamine N-acetyltransferases (NATs) are phase II xenobiotic metabolizing enzymes, catalyzing acetyl-CoA-dependent N- and O-acetylation reactions. All NATs have a conserved cysteine protease-like Cys-His-Asp catalytic triad inside their active site cleft. Other residues determine substrate specificity, while the C-terminus may control hydrolysis of acetyl-CoA during acetyltransfer. Prokaryotic NAT-like coding sequences are found in >30 bacterial genomes, including representatives of Actinobacteria, Firmicutes and Proteobacteria. Of special interest are the nat genes of TB-causing Mycobacteria, since their protein products inactivate the anti-tubercular drug isoniazid. Targeted inactivation of mycobacterial nat leads to impaired mycolic acid synthesis, cell wall damage and growth retardation. In eukaryotes, genes for NAT are found in the genomes of certain fungi and all examined vertebrates, with the exception of canids. Humans have two NAT isoenzymes, encoded by highly polymorphic genes on chromosome 8p22. Syntenic regions in rodent genomes harbour two Nat loci, which are functionally equivalent to the human NAT genes, as well as an adjacent third locus with no known function. Vertebrate genes for NAT invariably have a complex structure, with one or more non-coding exons located upstream of a single, intronless coding region. Ubiquitously expressed transcripts of human NAT1 and its orthologue, murine Nat2, are initiated from promoters with conserved Sp1 elements. However, in humans, additional tissue-specific NAT transcripts may be expressed from alternative promoters and subjected to differential splicing. Laboratory animals have been widely used as models to study the effects of NAT polymorphism. Recently generated knockout mice have normal phenotypes, suggesting no crucial endogenous role for NAT. However, these strains will be useful for understanding the involvement of NAT in carcinogenesis, an area extensively investigated by epidemiologists, often with ambiguous results.

Background-Arylamine N-acetyltransferases in humans (NAT1 and NAT2) catalyse the acetylation of arylamines including food derived heterocyclic arylamine carcinogens. Other substrates include the sulphonamide 5-aminosalicylic acid (5-ASA), which is an NAT1 specific substrate; N-acetylation of 5-ASA is a major route of metabolism. NAT1 and NAT2 are both polymorphic. Aims-To investigate NAT expression in apparently healthy human intestines in order to understand the possible role of NAT in colorectal cancer and in the therapeutic response to 5-ASA. Methods-The intestines of four organ donors were divided into eight sections. DNA was prepared for genotyping NAT1 and NAT2 and enzymic activities of NAT1 and NAT2 were determined in cytosols prepared from each section. Tissue was fixed for immunohistochemistry with specific NAT antibodies. Western blotting was carried out on all samples of cytosol and on homogenates of separated muscle and villi after microdissection. Results-NAT1 activity of all cytosols was greater than NAT2 activity. NAT1 and NAT2 activities correlated with the genotypes of NAT1 and NAT2 and with the levels of NAT1 staining determined by western blotting. The ratio of NAT1:NAT2 activities showed interindividual variations from 2 to 70. NAT1 antigenic activity was greater in villi than in muscle. NAT1 was detected along the length of the villi in the small intestine. In colon samples there was less NAT1 at the base of the crypts with intense staining at the tips. Conclusions-The interindividual variation in NAT1 and NAT2 in the colon could aVect how individuals respond to exposure to specific NAT substrates including carcinogens and 5-ASA. (Gut 1998;42:402-409)

No abstract