Toxicogenomics-based Study On Toosendan Fructus-induced Liver Injury

There are increasing case reports about liver injury induced by traditional Chinese medicine(TCM),therefore intensive study on TCM-induced liver injury has become one of hot issues in the field of safety evaluation of TCM.Toosendan Fructus(TF)is described as a slightly toxic traditional Chinese medicine in the current Chinese Pharmacopoeia(2010),several reports had demonstrated that TF can induce liver toxicity both in vivo and in vitro studies,however,as one of the most common TCM that cause liver damage,its toxic components and mechanism remain largely unknown.In the present study,an integrated microRNA(miRNA)-mRNA approach along with conventional toxicology assessments was applied to investigate the TF-induced liver injury in mice,which aimed to reveal the dose-and time-dependent manner of TF-induced liver injury as well as the mechanisms of the liver toxicity.The study mainly involved the following three parts:1.TF water extract induced liver injury in mice.The integrated microRNA-mRNA approach combined with conventional toxicology assessments was performed.The results suggested that the oxidative stress-induced hepatocytes necrosis may be the main mechanism of TF water extract-induced liver injury.2.TF ethyl acetate extract induced liver injury in mice.The integrated microRNA-mRNA approach combined with conventional toxicology assessments was also applied.The results indicated that lipid metabolism disorders play critical roles in TF ethyl acetate extract-induced liver injury,whereas a large number of drug-metabolizing enzyme and several nuclear receptors were also involved in the process.3.Toosendanin induced liver injury in mice.Results from both conventional toxicology assessments and mRNA microarray analysis revealed that toosendanin-induced liver injury has a dose-dependent response.Moreover,alterations of the expressions of whole mRNAs and miRNAs showed a time-dependent manner.Further study revealed that liver cell necrosis and lipid metabolism disorder were the leading causes of toosendanin-induced liver injury.The mitochondrial dysfunction may also be one of the reasons for the liver damage.Cholesterol biosynthesis and p53 signaling pathway may participate in the progress of liver regeneration after liver injury.