Temporal changes of hepatic drug-metabolizing enzymes mediated by hepatic ischemia-reperfusion injury and the protective effect of Oridonin

Hepatic ischemia-reperfusion injury (IRI) is a common complication associated with metabolic disturbances and postoperative liver failure. Despite its prevalence, there is still a significant gap in understanding the changes in hepatic drug-metabolizing enzymes-specifically cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs)-that occur due to hepatic IRI and in identifying effective treatment strategies. This study highlights the temporal changes in the expression and activity of CYPs and UGTs mediated by hepatic ischemia-reperfusion injury, demonstrating a correlation between these enzymatic changes and indicators of liver injury. Our findings demonstrate that Oridonin (ORI), a natural monomer derived from the traditional Chinese medicinal herb Rabdosia rubescens, has notable anti-inflammatory and antioxidant properties. ORI was found to counteract the adverse effects of hepatic IRI on CYPs and UGTs, thus alleviating the metabolic disturbances associated with the injury. Moreover, ORI effectively inhibits inflammatory responses, oxidative stress, and apoptosis related to hepatic IRI. It does this by suppressing the NLRP3 inflammatory pathway, activating the Nrf2 endogenous antioxidant pathway, and modulating the levels of key proteins such as Bcl-2. ORI also demonstrated efficacy in reducing inflammation in a cell hypoxia/reoxygenation (H/R) model. These results suggest that ORI holds promise as a therapeutic candidate for the treatment of hepatic IRI.