Acetaminophen-induced Hepatotoxicity In Rats Research Articles

Therapeutic effects of cimetidine on acetaminophen-induced hepatotoxicity in rats

Therapeutic effects of cimetidine on acetaminophen-induced hepatotoxicity in rats

Protective Effect of Butylated Hydroxyanisole and Butylated Hydroxytoluene against Acetaminophen-Induced Hepatotoxicity in Rats

We assessed the protective effect of the dietary antioxidants, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) against acetaminophen (APAP)-induced hepatotoxicity. After giving diets containing BHA (0.5%), BHT (0.5%) to male Wistar rats for 7 days, they were fasted for 16 h and then intraperitoneally injected with APAP (0.5g/kg). The severity of the hepatic injury was inferred from the plasma alanine aminotransferase and aspartate aminotransaferase levels 24 h later. The results indicated that BHA and BHT significantly protected the rats against APAP hepatotoxicity. Upon investigating the mechanism of the protective action of BHA and BHT, the hepatic glutathione (GSH) levels decreased to the same degree in the APAP, BHA + APAP, and BHT + APAP groups 2 h after the injection of APAP, while the GSH levels started to recover in all groups at 6 h, but increasing faster in the BHA + APAP and BHT + APAP groups than in the APAP group. As compared with the control group, the hepatic cytochrome P450 (CYP) 2E1 levels tended to be about 20% higher in the BHA + APAP group from 2 to 24 h, and about 30% higher in the BHT + APAP group only at 24 h. These results suggest that the protection against APAP-induced hepatotoxicity provided by BHA and BHT is partly due to rapid recovery of the hepatic glutathione levels but does not involve changes in the CYP2E1 levels.

Hepatoprotective and antioxidant effects of Alnus japonica extracts on acetaminophen‐induced hepatotoxicity in rats

The stem bark of the Betulaceae plant Alnus japonica, which is indigenous to Korea, has been used as a popular folk medicine for hepatitis and cancer. In this study, the antioxidant activity of the crude extract and the hepatoprotective activities on acetaminophen (AAP)-induced toxicity in the rat liver were evaluated. We investigated the effect of the methanol (AJM) and solvent fracton of the stem bark of Alnus japonica (AJ) on AAP-induced hepatotoxicity in rats. In rat hepatocyte culture, pretreatment with AJM (50, 100, 150 and 200 microg/ml) significantly decreased the cytotoxicity of AAP in a dose-dependent manner. The pretreated with EtOAc and BuOH fraction led to an increase in free radical scavenging activity and a decrease in inhibition of lipid peroxidation, both superoxide dismutase and catalase prevent the hepatotoxicity by AAP in the treatment of A. japonica fraction. We conclude that AJ is an important antioxidant in AAP-induced live hepatotoxicity and that extract of AJM plays a hepatoprotective effects in the against AAP-induced cytotoxicity in cultured rat hepatocytes in vitro. Pending more evaluation for safety and efficacy, AJ can potentially be used in mitigating AAP-induced hepatotoxicity.

Hepatoprotective activity of Centaurium erythraea on acetaminophen-induced hepatotoxicity in rats.

The methanol extract of the leaves of Centaurium erythraea L. (Gentianaceae) was evaluated for hepatoprotective activity against acetaminophen-induced liver toxicity in rats. An oral dose of 300 mg/kg/day for 6 days or a single dose of 900 mg/kg for 1 day exhibited a significant protective effect by lowering serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH). The activity of the extract was supported by histopathological examination of liver sections.

361 Probiotics effects on acetaminophen-induced hepatotoxicity in rat

361 Probiotics effects on acetaminophen-induced hepatotoxicity in rat

Protective Effect of Stiripentol on Acetaminophen-Induced Hepatotoxicity in Rat

Acetaminophen (APAP) is mainly eliminated at a therapeutic dose through glucuronidation and sulfatation and a small fraction is oxidized by cytochromes P450 (CYP) 2E1, 3A4, and 1A2 to N-acetyl-p-benzoquinone-imine (NAPQI), a highly reactive metabolite further conjugated with glutathione into APAP–GSH, and then metabolized to APAP–cystein and APAP–mercapturate excreted in urine. After APAP overdose, the glucuronidation and sulfatation pathways are saturated and the production of NAPQI increases, causing hepatic injury. Stiripentol (STP); (200 mg/kg), an anticonvulsant drug inhibitor of CYP1A2 and CYP3A4 in vivo in humans was tested against APAP-induced toxicity in rat in comparison with N-acetylcysteine (NAC; 100 mg/kg). The mortality rates 24 h after APAP overdose (2 × 500 mg/kg) were 63% (control), 38% (NAC), 0% (STP), and 4% (STP + NAC). The mean plasma transaminase concentrations 5 and 24 h after overdose were significantly higher in control than in STP and NAC groups. The percentage of rats without microscopic liver necrosis 5 h after APAP overdose was significantly higher in rats receiving STP (100%), NAC (83%), or STP + NAC (83%) than controls (42%). In another experiment, four similar groups were administered 50 mg/kg APAP. Plasma AUC0–5 h for APAP–GSH, APAP–cystein, and APAP–mercapturate as well as urine APAP–mercapturate mean amounts were significantly lower in STP animals than in the other groups. STP (200 mg/kg) inhibited NAPQI synthesis through CYP inhibition, thus preventing both liver necrosis and mortality in rats.

Protective effect of S-(1,2-dicarboxyethyl)glutathione, an intrinsic tripeptide in liver, heart and lens, and its esters on acetaminophen-induced hepatotoxicity in rats.

The administration of acetaminophen (APAP, 500 mg/kg, i.p.) produced liver necrosis and increased aspartate aminotransaminase (AST) activity in serum. The pretreatment of S-(1,2-diethoxycarbonyl)glutathione isopropyl ester (DCE-Et-GS iPr, 0.5 mmol/kg, p.o.) prevented hepatic necrosis and the elevation of serum AST activity by 99.9%. DCE-Et-GS iPr inhibited APAP-induced hepatotoxicity much more strongly than reduced glutathione (GSH), DCE-GS and other esters of DCE-GS. To clarify this protective effect, the hepatic GSH concentration was determined 2h after APAP administration. It was found that the DCE-Et-GS iPr administration significantly inhibited the GSH depletion caused by APAP, suggesting that the protective effect of DCE-Et-GS iPr on APAP-induced hepatotoxicity was due, at least in part, to the retention of hepatic GSH level.

Preventive effect of gomisin A, a lignan component of shizandra fruits, on acetaminophen-induced hepatotoxicity in rats

The preventive effect of gomisin A, a lignan component of shizandra fruits, on acetaminophen-induced hepatotoxicity in rats was examined by histological and biochemical analysis. Acetaminophen at a dose of 750 mg/kg was administered to male Wistar rats with or without pretreatment with 50 mg/kg of gomisin A. Gomisin A inhibited not only the elevation of serum aminotransferase activity and hepatic lipoperoxides content, characteristic of acetaminophen administration, but also the appearance of histological changes such as degeneration and necrosis of hepatocytes. However, gomisin A did not affect the decrease in liver glutathione content. These results suggest that gomisin A protects the liver from injury after administration of acetaminophen through the suppression of lipid peroxidation.

Early inhibition of the [formula omitted] ion pump during acetaminophen-induced hepatotoxicity in rat

The status of Na+ regulation was examined during early stages of alkylation insult to rat liver. Na+K+-ATPase activity in plasma membranes declined by 52% within 3 hr of treatment with 850 mg/kg acetaminophen. This loss preceded the release of alanine aminotransferase (2880 ± 1550 U/ml) and necrosis (2+) seen at 24 hr. Activities of 5′-nucleotidase and Mg2+-ATPase and recovery of plasma membranes were comparatively unchanged at 3 hr. Because damage to Na+K+-ATPase appeared early in the pathogenesis of acetaminophen hepatotoxicity, loss of hepatocellular Na+ regulation could represent one of the critical molecular consequences of lethal alkylation by acetaminophen.

Interaction of Acute Ethanol Administration with Acetaminophen Metabolism and Toxicity in Rats Fed Alcohol Chronically

In rats fed alcohol chronically, acetaminophen induced severe hepatotoxicity as judged by serum enzyme activities, liver histology, and mortality, whereas in both rats fed alcohol chronically and in their pair-fed controls, acute ethanol administration decreased acetaminophen hepatotoxicity. Since acetaminophen hepatotoxicity is increased in rats fed alcohol chronically and acute ethanol has been shown to inhibit the biotransformation of acetaminophen to reactive metabolite(s) by mixed function oxidation, we postulate that acute ethanol administration decreases acetaminophen-induced hepatotoxicity in rats fed alcohol chronically by inhibiting the enhanced production of toxic metabolites.