Metabolomic analysis of arginine metabolism in acute hepatic injury in rats

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  • Saitoh Wataru
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo
  • Yamauchi Shusuke
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo
  • Watanabe Kyoko
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo
  • Takasaki Wataru
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo
  • Mori Kazuhiko
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo

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To clarify the relationship between arginine metabolism and hepatic injury, metabolomic analysis was performed in rats treated with 3 representative hepatotoxicants, monocrotaline (MCT), concanavalin A (ConA), and α-naphthyl isothiocyanate (ANIT); or a myotoxicant, tetramethyl-p-phenylenediamine (TMPD). A single dose of MCT, ConA, or ANIT dose-dependently induced hepatocellular necrosis accompanied by decreased blood arginine and increased blood alanine aminotransferase (ALT) and arginase. A close correlation was detected between arginine and ALT (r = -0.746, -0.795, -0.787 for MCT, ConA, ANIT, respectively) or between arginine and arginase (r = -0.605, -0.808, -0.672 for MCT, ConA, ANIT, respectively) in all three hepatic injury models. In contrast, neither hepatocellular necrosis nor alterations in arginine were found in the skeletal muscle injury model, although ALT was slightly increased. An in vitro assay revealed that blood samples obtained from ConA-treated rats transformed external arginine to ornithine, and the reaction was totally inhibited by an arginase inhibitor. These results suggest that blood arginase plays a crucial role in arginine metabolism associated with hepatic injury. In metabolomic analysis, nearly 450 endogenous metabolites were identified in blood obtained from all the models. Among the 13 metabolites involved in arginine metabolism, decreased arginine and increased ornithine occurred in common in the hepatic injury models, whereas citrulline and other metabolites were not altered. These results indicate that arginine metabolism, especially the arginine-to-ornithine pathway, is altered in association with acute hepatic injury. Furthermore, blood arginine and ornithine are possibly specific biomarkers for hepatic injury.

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