Metabolomic study on the susceptible factors of idiosyncratic Traditional Chinese Medicine-induced liver injury: Exemplification of a Polygonum multiflorum preparation

The underlying mechanism(s) that govern idiosyncratic drug-induced liver injury (IDILI) have remained poorly defined. Several studies have shown that IDILI was caused by body diathesis, environment, metabolism, immunization, etc. However, the underlying mechanism(s) of IDILI was still ambiguous, which led to an unsolved issue in clinical toxicology. Understanding of such mechanisms is critical not only for the prevention of such DILI adverse effect as well as the clinical diagnosis, intervention or management of the affected individuals. In this study, we carried out a metabolomic study on mice treated with Runzao Zhiyang Capsule (RZZY), since Polygonum multiflorum , a key ingredient in this preparation, is known to cause DILI. Clinical case analysis showed that a small number of patients developed drug-induced liver injury (DILI) in a dose-independent manner. Meanwhile, the affected individuals often exhibited skin conditions associated with features of abnormal inflammatory responses. In normal mice, treatment with RZZY alone had no significant effects on biochemical indices of liver function, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. At the same time, it had no significant effects on liver histopathology either. Moreover, we used non-toxic dose of lipopolysaccharide (LPS) pretreatment to produce mild inflammatory stress mice model, which showed no significant liver injury phenotype, except for a small number of inflammatory immune cells infiltration in portal areas of liver. However, by metabolomics profiling, we found significant alterations of plasma metabolites in the LPS treated mice, including up-regulated histidine and alanine metabolic pathways ( P (P beta -alanine, l -histidine, cortexolone, cortisone, dihydrocortisol, melatonine and 18-hydroxycorticosterone, which may provide potential application value for recognition of susceptible individuals in clinical.