Arylamine N‐acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery

Abstract

Arylamine N‐acetyltransferases (NAT s) are polymorphic drug‐metabolizing enzymes, acetylating arylamine carcinogens and drugs including hydralazine and sulphonamides. The slow NAT phenotype increases susceptibility to hydralazine and isoniazid toxicity and to occupational bladder cancer. The two polymorphic humanNATloci show linkage disequilibrium. All mammalianNatgenes have an intronless open reading frame and non‐coding exons. The human gene products NAT1 and NAT2 have distinct substrate specificities:NAT2 acetylates hydralazine and human NAT1 acetylates p‐aminosalicylate (p‐AS) and the folate catabolite para‐aminobenzoylglutamate (p‐abaglu). Human NAT2 is mainly in liver and gut. Human NAT1 and its murine homologue are in many adult tissues and in early embryos. HumanNAT1is strongly expressed in oestrogen receptor‐positive breast cancer and may contribute to folate and acetyl CoA homeostasis.NAT enzymes act through a catalytic triad of Cys,His and Asp with the architecture of the active site‐modulating specificity. Polymorphisms may cause unfolded protein. The C‐terminus helps bind acetyl CoA and differs among NATs including prokaryotic homologues.NAT inSalmonella typhimurium supports carcinogen activation and NAT in mycobacteria metabolizes isoniazid with polymorphism a minor factor in isoniazid resistance. Importantly,natis in a gene cluster essential forMycobacterium tuberculosis survival inside macrophages.NAT inhibitors are a starting point for novel anti‐tuberculosis drugs. Human NAT1‐specific inhibitors may act in biomarker detection in breast cancer and in cancer therapy.NAT inhibitors for co‐administration with 5‐aminosalicylate (5‐AS) in inflammatory bowel disease has prompted ongoing investigations of azoreductases in gut bacteria which release 5‐AS from prodrugs including balsalazide.