Paracetamol (acetaminophen)-induced toxicity: Molecular and biochemical mechanisms, analogues and protective approaches

An overview is presented on the molecular aspects of toxicity due to parace tamol (acetaminophen) and structural analogues. The emphasis is on four mai n topics, that is, bioactivation, detoxication, chemoprevention, and chemop rotection. In addition, some pharmacological and clinical aspects are discu ssed briefly. A general introduction is presented on the biokinetics, biotr ansformation, and structural modification of paracetamol. Phase II biotrans formation in relation to marked species differences and interorgan transpor t of metabolites are described in detail, as are bioactivation by cytochrom e P450 and peroxidases, two important phase I enzyme families. Hepatotoxici ty is described in depth, as it is the most frequent clinical observation a fter paracetamol-intoxication. In this context, covalent protein binding an d oxidative stress are two important initial (Stage I) events highlighted. In addition, the more recently reported nuclear effects are discussed as we ll as secondary events (Stage II) that spread over the whole liver and may be relevant targets for clinical treatment. The second most frequent clinic al observation, renal toxicity, is described with respect to the involvemen t of prostaglandin synthase, N-deacetylase, cytochrome P450 and glutathione S-transferase. Lastly, mechanism-based developments of chemoprotective age nts and progress in the development of structural analogues with an improve d therapeutic index are outlined.