The chemical and molecular basis of the prevention of drug-induced liver injury by Nrf2. (360G-Wellcome-079674_Z_06_Z)

Drug-induced liver injury (DILI) is a major public health concern. Many drugs and chemicals, including the widely used analgesic paracetamol undergo metabolic activation in the liver to toxic metabolites. The human liver has evolved multiple systems to protect itself from chemical stress induced by chemicals and their metabolites. It has been proposed that a major mechanism for the up regulation of proteins that catalyse the bioinactivation of drugs (and their toxic metabolites), such as paracet amol, involves the redox sensitive Keap1-Nrf2-ARE signalling pathway which is thought to be activated by chemical modification of critical cysteine residues in Keap1. The purpose of our work is to understand the chemical and cellular signalling systems that determine DILI, from the initial contact of ultimate chemical toxin with target protein(s) through to pathological outcome. In this study we will focus on the earliest, dose-dependent, chemical interaction of paracetamol, and other relevant h epatotoxins with Nrf2 and Keap1. We will define the chemical and molecular mechanisms of protein modification that regulate the Nrf2-Keap1-ARE pathway and the consequent levels of defence gene induction, in relation to the level of chemical stress and the subsequent modulation of toxicological outcome.