Study On The Safety Re-evaluation Of CX

Objective: By the safety re-evaluation of CX to figure out the cause on the liver toxicity and to provide the clinical medication guidance. Methods:(1) HL-7702 cells model were used to investigate the liver cytotoxicity in vitro with various components in the prescription of CX. Cell viability, ALT, AST, and ALP levels were served as the detecting index to discover the potential toxicity of different components;(2) Use orthogonal experiment to decomposed CX was employed to investigate the liver cytotoxicity of different components of CX;(3) On the selected toxic medicinal materials, HL-7702 cells were used to further investigate the liver cytotoxicity of the origins, processing and other factors;(4) Perform chronic toxicity test for CX and toxic medicinal materials by checking the body weight, feeding, hematology, blood biochemistry, viscera index and histopathology of rats at the administration of 26 weeks and the withdraw after 13 weeks, respectively. Results: In vitro cytotoxicity screening results showed that Radix dipsaci and Fructus Psoraleae extract of CX have inhibitory effects on the growth of liver cells(IC50 = 4.98, 14.79 mg/m L). Decomposed CX variance analysis results showed that Fructus Psoraleae has significant effect on the liver toxicity CX(P<0.05) while decomposed CX without Fructus Psoraleae decrease the liver toxicity significantly(P<0.001). Therefore, we could conclude that the major toxic source of CX is from Fructus Psoraleae. Besides, no statistical differences in liver cytoxicity among different batches of Fructus Psoraleae were detected. However, the toxicity of processed Fructus Psoraleae decreased significantly compared to the unprocessed one(P<0.05). In vivo chronic toxicity test results show that all rats exhibit normal behavior and no death upon the administration. But reduced body weight and significant drop in food take was observed after the 3-4 weeks ofadministration each group(compared with the control group P<0.05). The results from the comparison of liver serum function related indexes in rats among CX and Fructus Psoraleae in high dose group and normal control group showed that the values of ALT, AST, Tbil, Dbil, TP, Glb, ALP and GGT increased at varies extent(P<0.05, P<0.01) while the values of Alb, A/G decreased at varies extent(P<0.05, P<0.01). The results from pathological examination showed that liver steatosis, mucosal erosion of small intestine inflammatory cell lesions and other infiltrations occurred in both CX and Fructus Psoraleae medium at high dose group, particularly more severe in the high dose group while less severe at low dose group and the decomposed CX without Fructus Psoraleae group. And the rats recovered after 13 weeks after withdraw of administration. Additionally, the unprocessed and processed Fructus Psoraleae groups showed obvious difference on body weight and histopathologic examination. Conclusions: The results from in vitro liver cells test showed that Fructus Psoraleae in CX exhibited significant liver toxicity. There were no significant differences in liver cell toxicity among different sources of Fructus Psoraleae while processed Fructus Psoraleae showed significantly decreased toxicity. The results from chronic toxicity test showed that the obvious toxicity to liver, small intestine and other organs occurred in rats among CX and Fructus Psoraleae medium at high dose. The toxicity of processed Fructus Psoraleae decreased significantly compared to the unprocessed one. The conclusion is that the major hepatotoxicity of CX comes from Fructus Psoraleae.