Higher Residual and Metabolic Dysfunction-Associated Fatty Liver Disease Risk of the <i>R-</i>Enantiomer of Famoxadone in Mice

Famoxadone (FAM) is a widely used chiral fungicide that may contribute to metabolic dysfunction-associated fatty liver disease (MAFLD). However, the enantioselective toxicity and mechanism of action of famoxadone enantiomers remain unclear. The enantioselective bioaccumulation of famoxadone in mice was investigated, and the hepatotoxicity of famoxadone enantiomers, specifically in relation to MAFLD, was evaluated by a 12 week oral exposure to Rac-FAM, <i>R-</i>FAM, and <i>S-</i>FAM. <i>R-</i>FAM showed higher bioaccumulation than <i>S-</i>FAM, in which the concentrations of <i>R-</i>FAM were 3.52 and 242.69 times that of <i>S-</i>FAM in the liver at the no observed effect level (NOEL) and 1/10 NOEL, respectively. <i>R-</i>FAM was found to cause an increase in liver coefficients, a decrease in the AST/ALT ratio, enhanced expression of inflammation-related genes, and lipid droplet accumulation in the liver. In contrast, mice treated with <i>S-</i>FAM exhibited no significant changes in the quality of these indicators. These results suggest that <i>R-</i>famoxadone is more likely to be the dominant enantiomer affecting the liver. Furthermore, the important functional genes involved in glucose and lipid metabolism were detected. It was found that <i>R-</i>FAM significantly disrupted key lipid metabolic pathways in the liver, including glucose metabolism, fatty acid synthesis, triglyceride synthesis, and fatty acid β-oxidation. Additionally, <i>R-</i>FAM induced more severe disruptions in liver glucose and lipid metabolism compared to <i>S-</i>FAM. These research findings provide insights into the enantioselective toxicity of famoxadone enantiomers in terms of their role in promoting MAFLD development, contributing to the safe utilization of the chiral pesticide famoxadone.