Females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR) is a broad-specificity sensor with species-specific responses to toxic agents. In this study, to examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXR-humanized (hPXR) transgenic mice administered oral binge EtOH were analyzed. hPXR females expressed higher levels of enzymes responsible for EtOH metabolism and key mediators of hepatocyte replication and repair. EtOH ingestion upregulated hepatic estrogen receptor α, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice.
See article at J Pharmacol Exp Ther 2015, 354:459–470.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics