Frontiers in Pharmacology (Mar 2016)

Untargeted metabolomics reveals dose-response characteristics for effect of rhubarb in a rat model of cholestasis

  • Cong-En eZhang,
  • Cong-En eZhang,
  • Ming eNiu,
  • Rui-yu eLi,
  • Rui-yu eLi,
  • Wu-Wen eFeng,
  • Wu-Wen eFeng,
  • Xiao eMa,
  • Xiao eMa,
  • Qin eDong,
  • Qin eDong,
  • Zhi-jie eMa,
  • Guang-Quan eLi,
  • Guang-Quan eLi,
  • Ya-Kun eMeng,
  • Ya eWang,
  • Ping eYin,
  • Lan-Zhi eHe,
  • Yu-Meng eLi,
  • Peng eTan,
  • Yan-ling eZhao,
  • Jia-Bo eWang,
  • Xiao-ping eDong,
  • Xiao-he eXiao

DOI
https://doi.org/10.3389/fphar.2016.00085
Journal volume & issue
Vol. 7

Abstract

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Cholestasis is a serious manifestation of liver diseases with limited therapies. Rhubarb, a widely used herbal medicine, has been frequently used at a relatively large dose for treating cholestasis. However, whether large doses are optimal and the therapeutic mechanism remain unclear. To explore these questions, the anti-cholestatic effect of five doses of rhubarb (0.21, 0.66, 2.10, 6.60, and 21.0 g/kg) in an alpha-naphthylisothiocyanate (ANIT)-induced rat model of cholestasis was examined by histopathology and serum biochemistry. A dose-dependent anti-cholestatic effect of rhubarb (0.21-6.6 g/kg) was observed, and an overdose of 21.0 g/kg showed a poor effect. LC-MS-based untargeted metabolomics together with pathway analysis were further applied to characterize the metabolic alterations induced by the different rhubarb doses. Altogether, 13 biomarkers were identified. The dose-response curve based on 9 important biomarkers indicated that doses in the 0.42-6.61 g/kg range (EC20-EC80 range, corresponding to 4.00-62.95 g in the clinic) were effective for cholestasis treatment. The pathway analysis showed that bile acid metabolism and excretion, inflammation and amino acid metabolism were altered by rhubarb in a dose-dependent manner and might be involved in the dose-response relationship and therapeutic mechanism of rhubarb for cholestasis treatment.

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