Establishment of a Stable Acute Drug-Induced Liver Injury Mouse Model by Sodium Cyclamate

Abstract

Objective: To establish a stable acute DILI mouse model and explore its possible pathogenesis. Methods: Mice were randomly divided into control, low-dose, middle-dose and high-dose sodium cyclamate groups. Mice in the model group were intraperitoneally injected with corresponding doses of sodium cyclamate, and in the control group intraperitoneally injected with 0.9% normal saline. The toxic effects of sodium cyclamate on liver, heart, kidney were evaluated by biochemical index level and histomorphologically observed. The expression of TNF-α and IL-1β were measured by immunohistochemistry. Results: 1. The level of ALT in the low-dose and middle-dose groups at 24h, 72h, 120h and 168h were increased, also in the highdose group at 24h, 72h and 120h. The level of AST in the low-dose group at 72h, 120h, 168h and in the middle-dose group at 168h were increased, also in the middle-dose and high-dose groups at 24h, 72h and 120h. The levels of CK, CK-MB and cTnT in the lowdose and middle-dose groups at 168h were increased, also in the high-dose group at 24h, 72h and 120h. 2. The damage of hepatocytes increased with the increase of sodium cyclamate dosage and treated time. 3. At 120h, the IOD/Area of TNF-α and IL-1β positive expression increased in the liver tissues with the increase of the dosage. In the heart and kidney tissues, the IOD/Area of TNF-α and IL-1β positive expression in the high-dose group increased significantly. In the kidney tissues, the IOD/Area of IL-1β positive expression in the middle-dose group increased significantly. Conclusion: Sodium cyclamate-induced acute DILI mouse model can be established by intraperitoneal injection of 6000 mg/kg/day sodium cyclamate for 5 days successfully. The toxicity of sodium cyclamate to liver showed a dose-response and time-response relationship. Sodium cyclamate induced liver, heart and kidney injury closely related to the inflammatory response mediated by TNF-α and IL-1β.