Host: The Japanese Society of Toxicology
Name : The 50th Annual Meeting of the Japanese Society of Toxicology
Date : June 19, 2023 - June 21, 2023
[Purpose]
cDNA-uPA/SCID mouse with a humanized-liver (PXB-mouse®) presents a fatty liver because of species specificity of growth hormone (GH) that suppress lipid synthesis in human hepatocytes. In this study, we aimed for determining an appropriate dosage of human-GH (hGH) for evaluation of human drug-induced fatty livers.
[Methods]
hGH was continuously administered for 14 days with osmotic pumps at predetermined dosages. Based on the results, TO901317 (TO), one of LXR agonists, was orally administered into hGH-administered PXB-mice. Long acting hGH drugs (Sogroya and Ngenla) were also subcutaneously injected for a minimally invasive treatment.
[Results and Discussion]
The improvement in hepatic steatosis was observed at 0.25 mg/kg or more hGH dosing. Especially, serum hGH levels in PXB-mice administered with 0.25 mg/kg were comparable to physiological levels in human. Based on these results, TO was orally co-administrated (0.25 mg/kg hGH for 14 days, and 10, 30, 100 mg/kg TO for 4 days), presenting TO-dosage-dependent excitation of lipid accumulation in humanized livers. Besides, more sensitive evaluation of liver steatosis was constructed by a long-term co-administration of hGH (0.25 mg/kg, 4 weeks) and TO (30 mg/kg, 7 days). These results suggested that the hGH-administered PXB-mouse would be a valid model animal for the study of drug-induced fatty livers. Sogroya and Ngenla also improved fatty livers respectively.
[Conclusion]
We determined the appropriate hGH dose to PXB-mice that improves fatty livers and achieves blood hGH concentration comparable to the human physiological level. This hGH-administered PXB-mouse could be a valid evaluation model for drug-induced fatty livers. In addition, we are analyzing the expression levels of drug-metabolizing enzymes and transporters.
