ABSTRACT
Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10-15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury.
Subject(s)
Acetaminophen/pharmacology , Adaptation, Physiological/drug effects , Liver/metabolism , Proteome/metabolism , Animals , Cytochrome P-450 CYP2E1/metabolism , Liver/drug effects , Liver/enzymology , Male , Mice, Inbred C57BL , Proteomics , Rats , Signal Transduction/drug effectsABSTRACT
New biomarkers of drug-induced liver injury (DILI) are required in the clinic and in preclinical pharmaceutical evaluation. Liver-enriched microRNAs are promising serum biomarkers of acetaminophen-induced acute liver injury in mice. The utility of circulating microRNAs as biomarkers of human acute DILI is discussed in the context of correlation with existing biomarkers of liver injury and patient outcomes in acetaminophen toxicity, mechanisms of cellular microRNA release, and their potential advantages over current clinical biomarkers of DILI.
