Abstract
An overdose of acetaminophen results in liver injury in experimental animals and human. It is initiated by metabolic activation by cytochrome P450 enzymes into the reactive N-acetyl p-benzoquinone imine metabolite followed by its covalent binding to liver target proteins. However factors other than the covalent binding contribute to the severity of the toxicity and involvement of activated Kupffer cells and infiltrated macrophages has been demonstrated. These liver nonparenchymal cells produce and release the inflammatory mediators, reactive oxygen species, nitric oxide and cytokines, which are suggested to be involved in the liver injury. Liver mRNAs of interleukin-6 (IL-6), IL-10 and IL-11, which are classified as anti-inflammatory cytokines and are considered to suppress inflammatory tissue injury, increased markedly after the acetaminophen administration. Acetaminophen-induced liver injury was exaggerated in mice deficient in IL6 (IL-6-/ -mice) and IL-10/ -mice as compared with corresponding wild-type mice. Administration of recombinant human IL-11 protein prior to acetaminophen blocked the liver injury. Immunoblot analysis of liver homogenate indicated no significant effect of the perturbation of the cytokines on formation of acetaminophen-protein adduct. These results demonstrated protective role of these anti-inflammatory cytokines against the hepatotoxicity of acetaminophen, which is not due to effect on the metabolic activation. It also suggested involvement of proinflammatory cytokines in the pathogenesis of acetaminophen-induced liver injury, because they are regulated by anti-inflammatory cytokines.
