Human N-Acetyltransferases and Drug-Induced Hepatotoxicity

Abstract

There are a lot of pharmaceutical substances nowadays on the market. More than 1000 drugs have been implicated in causing liver diseases in more than one occasion. The liver is the most massive and important internal organ of human body. The morphological and functional integrity of the liver is vital to the health of the human organism. Xenobiotic biotransformation is the principal mechanism for maintaining homeostasis during exposure of organisms to small foreign molecules, such as drugs. Most drugs are lipophilic and they become more hydrophilic by xenobiotic metabolizing enzymes. Arylamine N acetyltransferases (NAT) convert aromatic amines or hydrazines to aromatic amides and hydrazides. A lot of generally used drugs contain aromatic amine or hydrazine groups. Drug-induced liver injury (DILI) is the grave problem in the present world. The frequency of DILI is 15-40 cases per 100000 persons per year with 6 % mortality rate on average. This review is devoted to the analyses of arylamine N-acetyltransferases role in DILI. The NAT gene polymorphism and slow phenotype are associated with predisposition to hepatotoxicity during drug-specific treatment. NAT activity is changed by smoking, viral infections and variety of drugs. It is shown that the involving of NAT in pathogenic processes of DILI such as inflammatory or immune response, formation reactive metabolites, oxidative stress, cholestasis.