Methods and Approaches to Study Metabolism and Toxicity of Acetaminophen

Although acetaminophen (also known as paracetamol) is a relatively safe and freely available analgesic, frequent organ toxicity (primarily in the liver) and admissions to emergency rooms occur. The aim of this chapter is to indicate selectively the most promising areas of research into the mechanisms of action of this drug and to highlight briefly new methodologies that are likely to maximize chances of filling gaps in our knowledge. As many other therapeutic and environmental chemicals mediate cell death and tissue damage by similar mechanisms as acetaminophen (i.e., via “reactive metabolites”), it is likely that any new information with respect to the toxicological mechanisms of acetaminophen will be generally applicable. The chapter highlights the metabolic scheme for both activation and detoxification of acetaminophen; summarizes current knowledge on the intracellular sequelae after exposure; assesses the relative importance of protein modification, oxidative stress, and mitochondrial injury in the mechanism of action; discusses evidence for the role of chemokines and cytokines in the “extrinsic” phase of aceta-minophen-induced liver injury; assesses the role of nitric oxide and other reactive nitrogen species in injury; and discusses new approaches to studying liver injury, including the use of transgenic animals, RNA interference, DNA microarrays, and proteomic approaches.