The Role Of Glucuronidation In Eriodictyol Alleviating Acetaminophen-induced Hepatotoxicity

ObjectiveAcetaminophen(APAP)is one of the most commonly used oral analgesics and antipyretics,but hepatotoxicity including liver failure may occur after an overdose.Current studies have confirmed that oxidative stress was one of the principal causes of acetaminophen hepatotoxicity.And compounds with antioxidant activity may have the ability to alleviate APAP-induced hepatotoxicity.Eriodictyol,a flavonoid component contained in Chinese herbal medicines and diets.Eriodictyol has anti-inflammatory and antioxidant bioactivities.However,the protective effect of eriodictyol on APAP-induced hepatotoxicity has not been reported yet.The purpose of this study was to identify the protective effect and mechanism of eriodictyol against APAP-induced hepatotoxicity.Methods1.Various administration routes analyses were used to determine the protective effects of eriodictyol against APAP-induced hepatotoxicity.2.Using microsomal incubation system,enzymatic kinetics,and a single-pass mice intestinal perfusion model to investigate the metabolic mechanism of eriodictyol.3.Pharmacokinetic-pharmacodynamic model(PK-PD),UGTs chemical inhibitor,and UGTIAs knockdown mice(Ugtl+/-)were used to confirm that the role of glucuronidation in eriodictyol alleviating APAP-induced hepatotoxicity.4.Using probe substrate incubation system,biochemical index kit and transferase-mediated deoxyuridine triphosphate-biotin nick end labeling(TUNEL)staining to investigate the hepatoprotective mechanism of eriodictyol.Results1.Protective effects were observed in intravenously and intraperitoneally but not in intragastrically administered eriodictyol.2.The results showed that eriodictyol was not metabolized by CYP450 and SULTs,but mainly metabolized by UGTs and produced two monoglucuronide metabolites.UGTIAs(mainly UGT1 A1,UGT1A9,UGT1A10)and UGT2B7 were likely the main contributors to glucuronidation of eriodictyol.3.PK-PD studies have shown that plasma and liver concentrations of eriodictyol were significantly greater than metabolites when eriodictyol agaist APAP-induced hepatotoxicity.After intravenous administration of glycyrrhetinic acid(GA),a UGTs enzyme inhibitor,the oral bioavailability and hepatoprotective effect of eriodictyol were significantly increased.In Ugtl+/-mice,intragastrically administered eriodictyol markedly attenuated APAP-induced hepatotoxicity,whereas no protection was observed in wild-type mice.Therefore,glucuronidation reduces the protective effect of eriodictyol in APAP-induced hepatotoxicity.4.The results showed that eriodictyol attenuated APAP-induced hepatotoxicity via reduction of toxic metabolites of APAP by the inhibition of Cyp2el and Cyp3a11 activities;reserve for glutathione(GSH)by improvement on glutathione peroxidase(GSH-Px),glutathione reductase(GR),and glutathione S-transferase(GST)activities;elevation of activity of superoxide dismutase(SOD);reduction of the level of malondialdehyde(MDA);and remission of hepatocyte apoptosis.ConclusionIn summary,these studies have demonstrated that eriodictyol has the ability to attenuate APAP-induced hepatotoxicity,and glucuronidation reduces the protective of eriodictyol in APAP-induced hepatotoxicity.At the same time,studies have shown that eriodictyol antagonizes APAP-induced hepatotoxicity by inhibiting the reduction of toxic metabolites;relieving glutathione consumption;and reducing oxidative stress.