Metabolomics‐guided amino acid analysis reveals acetaminophen overdose‐induced disruption of arginine metabolism in mouse

Abstract

Acetaminophen (APAP) overdose is a major cause of acute liver failure. Significant changes in lipids, glucose, and thiol antioxidants have been observed in APAP‐induced hepatotoxicity (AIH). However, the influences of AIH on amino acid metabolism are not well characterized. In this study, the profiles of free serum amino acids in the wild‐type (WT) and Cyp2e1‐null (KO) mice after APAP (400 mg/kg BW) treatment were defined through metabolomics‐guided biochemical analysis. Consistent to different sensitivity to AIH, serum amino acid levels differed greatly between WT and KO mice. Among observed changes in amino acids, APAP‐induced change in arginine was the most dramatic. After APAP treatment, serum arginine in WT mice became undetectable within 2 hours, while its level in KO mice was reduced at early time points but recovered quickly. This depletion of serum arginine in WT mice was well correlated to the increased arginase activity in serum, suggesting the release of arginase from the liver is the main cause of arginine depletion. Accompanying with rapid degradation of serum arginine, the distribution of arginine in WT mice as well as the levels of arginine metabolites was also dramatically affected. All these observations warrant further investigation on the role of arginine in AIH.