Abstract: OBJECTIVE: To investigate effects of metformin on alleviating cadmium-induced liver injury in mice. METHODS: Male wild-type (WT) and liver-specific Ppp2r1a knockout mice (HO) were randomly divided into 4 groups： control (solvent control)， cadmium treatment (1.5 mg/kg CdCl₂)， metformin treatment (100 mg/kg metformin)， and cadmium and metformin combined treatment (1.5 mg/kg CdCl₂， 100 mg/kg metformin). These mice were consecutively administrated for 7 days by intraperitoneal injection. The semiautomatic blood biochemical analyzer was used to examine levels of ALT，AST，and TG. H&E and oil red O staining were performed to observe pathological changes of liver tissues. Real-time quantitative fluorescence PCR (qPCR) was conducted to determine mRNA levels of cadmium-related transporters. After L02 human hepatocytes were exposed to CdCl₂ and/or metformin， cell viability was detected by CCK-8 kit， and intracellular calcium ion levels were evaluated by detecting the fluorescence intensity of Fluo-4 AM under a fluorescence microscope. RESULTS: Cadmium exposure increased the blood plasma ALT and AST levels in WT mice by 86.40% and 3.19%，respectively. These mice exhibited pathological changes such as hepatocyte injury，liver lipid degeneration and deposition，and liver injury. Moreover，these effects were more profound in HO mice than that in WT mice. Compared with the cadmium treatment group alone，metformin treatment led to the 61.14% and 44.02% decrease in the plasma ALT and AST levels，respectively. Correspondingly，the degree of hepatocyte necrosis，lipid degeneration and deposition were relieved. Compared with WT mice，the mRNA levels of zip14 and dmt1， which mainly mediate cadmium transport and absorption in liver， were increased in HO mice by 16.48% and 53.61%，respectively. Upon CdCl₂ exposure，the mRNA levels of zip14 and dmt1 were increased in HO mice by 47.32% and 136.23%，respectively，compared to that in WT mice. The fluorescence intensity in L02 cells treated with CdCl₂ was increased by 2.72 times，and the corresponding cell viability was decreased by 45.99%. Compared to that in CdCl₂-treatemnt alone，1 mmol/L and 2 mmol/L metformin treatment reduced the fluorescence intensity by 40.77% and 54.17% ， respectively， and the corresponding cell viability were increased by 59.28% and 89.78%. CONCLUSION: PP2A activities were involved in CdCl₂-induced liver injury in mice by regulating the expression of cadmium transporter. Metformin could alleviate CdCl₂-induced hepatotoxicity，partly by inhibiting absorption of cadmium ions in hepatocytes.

Key words: CdCl₂, hepatotoxicity, protein phosphatase 2A, metformin