Clinical relevance of N-acetyltransferase (NAT2) genetic polymorphism

Polymorphic N-acetyltransferase (NAT2) is involved in the metabolism of several compounds relevant in pharmacology or toxicology, with diverse clinical consequences. Inter-ethnic variations in distribution of the; acetylation phenotype are significant. The caffeine test is most often used to assess the acetylation phenotype and to identify rapid and slow acetylators. The NAT2 phenotypes could account for the increased risk of certain side effects in slow acetylators treated with isoniazid (particularly peripheral neuropathies and lupus erythematosus), although therapeutic efficacy seems to be independent of the acetylation status. Hypersensibility reactions with sulfonamides (including Lyell and Stevens-Johnson syndromes) are more frequent in slow acetylators, who also show poor tolerance to sulfasalazine and dapsone. In contrast, myelotoxicity induced by amonafide is more frequent in rapid acetylators, probably because of increased production of a toxic metabolite of the drug. In carcinogenesis, NAT2 may play a protective role,against bladder-cancer, although studies have shown, contradictory results. Slow acetylators may have a risk of developing primitive liver cancer. For lung cancer, data are not conclusive, but slow acetylation status may predispose to mesothelioma in subjects exposed to asbestos. No relation has been found between acetylation phenotype and breast cancer. Contradictory results were reported on its role in colorectal cancer. Nonsmoking type I diabetics may be at increased risk of nephropathy if they are rapid acetylators. Parkinson's disease may be more frequent among slow acetylators, but again, data have shown contradictory results. Finally, a poor acetylator phenotype may predispose to atopic diseases.