Protective effect of hyperoside against acetaminophen (APAP) induced liver injury through enhancement of APAP clearance.

Acetaminphen (APAP) overdose leads to severe hepatotoxicity. Apocynum venetum L. (A. venetum) possess potent hepatoprotective effect. Hyperoside is one of the major compounds exist in Apocynum venetum L. and might be a potential agent to protect against APAP-induce liver injury. In this study, we investigated the effect of hyperoside on APAP hepatotoxicity in mice. Mice were treated intragastrically with hyperoside (10, 50 or 100 mg/kg) for 3 days before APAP (300 mg/kg) injection. APAP alone caused severe liver injury characterized by significantly increased serum aminotransferase levels, hepatic malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) formation, as well as liver superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH) depletions. Hyperoside significantly attenuated APAP-induced liver damages in a dose dependent manner, and 100 mg/kg was the most effective dose. Further study confirmed that hyperoside was able to increase activities and mRNA expressions of uridine diphoshate glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), as well as to inhibit CYP2E1 activities, and thereby suppressed toxic intermediate formation and promoted APAP hepatic detoxification. Nrf-2 activation might be involved in hyperoside induced up-regulation of phase II enzymes. Collectively, our data provide evidence that hyperoside protected the liver against APAP induced injury mainly by accelerating APAP harmless metabolism, implying that hyperoside can be considered as a potential natural hepatoprotective agent.

Xie W ，Jiang Z ，Wang J ，Zhang X ，Melzig MF ... -  《-》

Hepatoprotective effect of isoquercitrin against acetaminophen-induced liver injury.

Acetaminophen (APAP) overdose leads to severe hepatotoxicity. Isoquercitrin exhibited potential hepatoprotective effect in our previous study. The present investigation aimed to evaluate the effect of isoquercitrin against APAP induced liver injury and to explore its possible mechanism. Mice were treated intragastrically with isoquercitrin (10, 20, or 50mg/kg) for 3days before APAP (300mg/kg) injection. After 24h from APAP treatment, the levels of serum aminotransferase, hepatic oxidative stress and nitrosative stress biomarkers were determined by commercial kits or western bolt. Activities of UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs) and cytochrome 2E1 (CYP2E1) were evaluated using ELISA methods and standard biochemical procedures. Subsequently, the protein and mRNA levels of inflammatory factors including TNF-α, IL-1β, IL-6 and iNOS were determined using ELISA methods, western blot or real-time PCR. The effect of isoquercitrin on APAP activated NFκB/MAPK pathway was assessed by western bolt. Isoquercitrin pretreatments markedly attenuated APAP induced hepatic oxidative stress, nitrosative stress and centrilobular necrosis. In addition to potent antioxidant activity, isoquercitrin was able to regulate the activities of SULTs and CYP2E1, therefore promoted APAP hepatic detoxification. The anti-inflammatory activity of isoquercitrin which involved in the amelioration of iNOS, TNF-α, IL-1β and IL-6 production via the blockade of NF-κB and MAPK pathways also responsible for its hepatoprotective effect. Our data evidenced that isoquercitrin protected liver from APAP induced injury though inhibition of oxidative stress, nitrosative stress and inflammation, as well as regulation of APAP metabolism, suggesting that isoquercitrin could be a potential hepatoprotective agent.

Xie W ，Wang M ，Chen C ，Zhang X ，Melzig MF ... -  《-》

Apocynum venetum Attenuates Acetaminophen-Induced Liver Injury in Mice.

Xie W ，Chen C ，Jiang Z ，Wang J ，Melzig MF ，Zhang X ... -  《-》

Protection afforded by pre- or post-treatment with 4-phenylbutyrate against liver injury induced by acetaminophen overdose in mice.

Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is a widely used analgesic/antipyretic drug with few adverse effects at therapeutic doses; suicidal or unintentional overdose of APAP frequently induces severe hepatotoxicity. To explore a new and effective antidote for APAP hepatotoxicity, this study examined the effects of sodium 4-phenylbutyrate (4-PBA) on liver injury induced by APAP overdose in mice. Liver injury was induced in C57BL/6 male mice by intraperitoneal injection of APAP (400mg/kg). The effects of 4-PBA (100-200mg/kg) treatment at 1h before the APAP injection were evaluated with serum alanine aminotransferase (ALT) and blood ammonia levels, hepatic pathological changes, including histopathology, DNA damage, nitrotyrosine formation, and mRNA or protein expression involved in the development of hepatotoxicity, such as X-box binding protein-1 (XBP1), c-Jun N-terminal kinase (JNK), C/EBP homologous protein (CHOP) and B-cell lymphoma 2 interacting mediator of cell death (Bim). In addition, glutathione depletion and CYP2E1 protein expression, which are measures of the metabolic conversion of APAP to a toxic metabolite, were examined. Furthermore, we examined the effects of post-treatment with 4-PBA against APAP-induced hepatotoxicity in mice. When administered at 1h before APAP injection, 4-PBA significantly prevented the increase in serum ALT and blood ammonia levels, centrilobular necrosis of hepatocytes, DNA fragmentation, and nitrotyrosine formation induced by APAP in mice. 4-PBA also inhibited hepatic Xbp1 mRNA splicing and JNK phosphorylation induced by APAP, but did not suppress CHOP and Bim mRNA and protein expression. In addition, 4-PBA had little effect on hepatic glutathione depletion and CYP2E1 expression, parameters of toxic APAP metabolite production. Post-treatment with 4-PBA administration at 1 or 2h after APAP injection also attenuated the increase in serum ALT and blood ammonia levels and hepatic pathological changes in APAP-induced hepatotoxicity in mice. Although post-treatment with 4-PBA did not show any effects on hepatic Xbp1 mRNA splicing and JNK phosphorylation, it drastically attenuated the DNA fragmentation induced by APAP. The precise molecular mechanisms of the protection afforded by 4-PBA against APAP hepatotoxicity in mice are unclear, but they seem to involve inhibition of hepatocellular DNA fragmentation. We suggest that 4-PBA is a promising candidate as an antidote against APAP-induced liver injury.

Shimizu D ，Ishitsuka Y ，Miyata K ，Tomishima Y ，Kondo Y ，Irikura M ，Iwawaki T ，Oike Y ，Irie T ... -  《-》

Osthole prevents acetaminophen-induced liver injury in mice.

Cai Y ，Sun W ，Zhang XX ，Lin YD ，Chen H ，Li H ... -  《-》