Abstract: Objective To clarify the dose-time-effect relationship of tripterygium glycosides (TG) hepatotoxicity, investigate the mechanism of TG hepatotoxicity in rats based on the regulation of cytochrome P450 enzymes, and explore the mechanism of toxicity reduction of compound glycyrrhizin (CG) with TG in order to ensure safe clinical applications of TG. Methods Thirty male SD rats were randomly divided into the control group, TG 189.0 mg·kg^-1 group, TG 472.5 mg·kg^-1 group, and TG 189.0 and 472.5 mg·kg^-1 respectively combined with CG 20.25 mg· kg^-1 groups according to body weight, with 6 rats in each. The drug was administered once daily for three weeks. The serum levels of total protein(TP)、albumin(ALB), aspartate aminotransferase(AST), and alanine aminotransferase(ALT)were measured at 1, 2, and 3 weeks after dosing, respectively. At the end of the last dose, liver coefficients were calculated and histopathological examinations were performed to detect the transcript levels of CYP2B1 and CYP3A1 genes. Results One week after administration, the serum levels of ALB in the TG 189.0 and 472.5 mg·kg^-1 groups became lower (P<0.05), but ALT in the TG 472.5 mg·kg^-1 group was increased (P<0.01). Three weeks after administration, the level of TP in the TG 189.0, and 472.5 mg·kg^-1 groups continued to decrease. After 3 weeks of coadministration with CG, the ALT level in the TG 472.5 mg·kg^-1 group decreased (P<0.01) while those of ALB and TP (P<0.05) increased compared with the same dose of TG used alone. After three weeks of administration, rats in the TG 189.0 mg·kg^-1 group showed slight swelling of hepatocytes and a small amount of lymphocyte infiltration in the confluent area while those in the TG 472.5 mg·kg^-1 group showed an increase in liver weight and liver coefficient compared with the control group (P<0.05, P<0.01). TG at doses of 189.0 and 472.5 mg·kg^-1 increased CYP2B1 and CYP3A1 mRNA levels in liver tissues of rats (P<0.05, P<0.01). CYP2B1 mRNA levels were down-regulated after the combination of TG and CG. Conclusion TG administered to rats at doses of 189.0 and 472.5 mg·kg^-1 for three consecutive weeks caused different degrees of liver injury. Hepatotoxicity of TG 472.5 mg·kg^-1 was more severe, and was more significant three weeks after administration than one week after administration, with a dose time effect relationship. Overexpression of CYP2B1 and CYP3A1 mRNA in rat hepatocytes is one of the mechanisms of toxicity. CG can reduce hepatotoxicity by downregulating the CYP2B1 mRNA level.

Key words: tripterygium glycosides, liver injury, drug metabolism enzyme, compound glycyrrhizin, compatibility attenuated, rat, P450 enzymes, rat