Abstract
Green tea polyphenols (GTPs) have been shown to exhibit diverse beneficial effects against a variety of diseases. Acetaminophen (APAP) overdose is one of the most frequent causes of drug-induced liver injury. In the current study, we aimed to investigate the protective effect of GTP on APAP-induced liver injury in mice and the underlying mechanisms involved. Male C57BL/6J mice were treated orally with different doses of GTP (37.5, 75, or 150 mg/kg) 4 h after APAP overdose (400 mg/kg) and continuously given every 8 h until sacrificed at 4, 12, 20, and 48 h after the first treatment of GTP. Survival rate and histological and biochemical assessments were performed to evaluate the APAP-induced liver injury. Protein expression of multiple drug metabolizing enzymes and transporters was measured to demonstrate the possible mechanisms involved. Our results revealed that administration of different doses of GTP significantly alleviated APAP-induced liver injury by improving the survival rate, hepatocellular necrosis, and ALT/AST/GSH levels after APAP overdose (400 mg/kg). The protein expression of APAP-induced drug transporters and metabolizing enzymes was mostly induced by GTP treatment, which was followed by reduction in drug transporters at the later time points. The current study collectively demonstrated that GTP protects against APAP-induced liver injury, possibly through regulating drug metabolizing enzymes and transporters after APAP overdose.
Highlights
Drug-induced liver injury has been identified as an important clinical issue which can be caused by various physician-prescribed medications, over-the-counter (OTC) medications, herbal medicines, and vitamin supplements [1]
It has been well established that metabolic activation of APAP to N-acetyl-p-benzoquinone imine (NAPQI), a toxic and highly reactive intermediate, by multiple cytochrome P450 enzymes serves as the critical step initiating the hepatotoxicity. e increasing amount of NAPQI depletes liver glutathione (GSH) and covalently binds to cellular proteins and DNA, which eventually results in oxidative stress, mitochondrial damage, and hepatocellular necrosis [2,3,4]
APAP was purchased from MCE Co. (China). e anti-mrp2, anti-cyp2e1, anti-cyp1a2, anti-cyp3a4, anti-P-gp, anti-ugt1a6, and anti-gapdh antibodies and goat anti-rabbit immunoglobulin G (IgG) were obtained from Abcam (Cambridge, UK). e anti-sult1a1 antibody was obtained from Bioss (Beijing, China). e gallic acid (GA), gall catechin (GC), epigallocatechin (EGC), catechin (C), caffeine (CAF), epicatechin (EC), epigallocatechin gallate (EGCG), gallate (GCG), epicatechin gallate (ECG), catechin gallate (CG), theaflavin (TF), theaflavin-3-gallate (TF-3-G), and theaflavin-3′-gallate (TF-3′-G) standards were all of chromatographic grade and purchased from Sigma-Aldrich
Summary
Drug-induced liver injury has been identified as an important clinical issue which can be caused by various physician-prescribed medications, over-the-counter (OTC) medications, herbal medicines, and vitamin supplements [1]. Acetaminophen (APAP) is a widely prescribed analgesic and antipyretic drug, which is relatively safe and effective when administered at therapeutic doses. E increasing amount of NAPQI depletes liver glutathione (GSH) and covalently binds to cellular proteins and DNA, which eventually results in oxidative stress, mitochondrial damage, and hepatocellular necrosis [2,3,4]. Increasing the expression of membrane transporters such as P-glycoprotein (P-gp) and multidrug resistance-associated proteins (Mrps) has been shown to facilitate the excretion of glucuronate and sulfate, and GSH conjugates from the liver [5]
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