MON-258 - CAR and ER a Help Regulate Acetaminophen Overdose Response and the Impact of Female Estrous Cycle in Regulating Overdose Response

Constitutive androstane receptor (CAR) and estrogen receptor alpha (ERa) essential nuclear receptors that regulate xenobiotic metabolism, hormone signaling, and hepatic stress responses. Although both CAR and ERa have been explored separately in acetaminophen overdose - CAR exacerbating necrosis and ERa ameliorating necrosis – their coordinated roles remain unclear. Sex hormones further complicate this relationship: estrogen can mitigate liver damage, while androgens often exacerbate it, yet how these hormones influence CAR and ERa signaling during APAP toxicity is not known. Importantly, no studies have examined CAR-ERa crosstalk in a female-specific system, despite clear evidence that sex differences alter acetaminophen metabolism and overdose injury response. We seek to identify how CAR and ERa coregulate APAP necrotic responses across estrous stages in female mice in response to cyclic hormone changes. Our preliminary data show that CAR is most active 6 and 24 hours after overdose while ERa is most active at 24 hours. This preliminary data points towards CAR and ERa being coordinative during APAP OD. Female mice will be staged using vaginal lavage and treated with acetaminophen at proestrus, estrus, metestrus, and diestrus. We expect for female mice’s cyclic hormones to impact the severity of the necrotic response during acetaminophen overdose- estrus and proestrus being the least necrotic and metestrus and diestrus being the most necrotic.

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