Carbon Tetrachloride Hepatotoxicity In Rats Research Articles

Ameliorative Effects of Pomegranate Molasses and Fig on Carbon Tetrachloride Hepatotoxicity in Rats

Ameliorative Effects of Pomegranate Molasses and Fig on Carbon Tetrachloride Hepatotoxicity in Rats

Ameliorative effects of pomegranate on carbon tetrachloride hepatotoxicity in rats: A molecular and histopathological study.

The present study aimed to investigate the molecular mechanism underlying the hepatoprotective effects of pomegranate (POM) against oxidative stress in a rat model of carbon tetrachloride (CCl4)-induced liver damage. Injection of rats with CCl4 resulted in hepatic inflammation and lipid accumulation via the upregulation of interleukin (IL)‑6 and sterol regulatory element‑binding protein 1c (SREBP‑1c) mRNA expression. CCl4 induced downregulation of the anti‑inflammatory factors alpha 2‑macroglobulin (α‑2M) and IL‑10 in comparison with the POM treated group. In addition, CCl4 induced downregulation of superoxide dismutase (SOD), glutathione S‑transferase (GST) and catalase (CAT) expression. Conversely, prior administration of POM counteracted the deleterious alterations induced by CCl4. POM downregulated CCl4-induced IL‑6 upregulation, normalized the increase in SREBP‑1c expression, and prevented CCl4‑induced α‑2M downregulation. POM counteracted CCL4‑induced alterations via immunosuppressive, anti‑inflammatory and regenerative effects by upregulating transforming growth factor‑β1, HSP70 and IL-10 mRNA expression. In addition, POM increased reactive oxygen species scavenging activity by augmenting the antioxidant defense mechanism against CCl4 hepatotoxicity, as demonstrated by detecting SOD, CAT and GST expression. These results confirm that, at the molecular level, POM exerts hepatoprotective effects against CCl4‑induced oxidative stress and liver tissue damage.

Long-Term Treatment with Shengmai San-Derived Herbal Supplement (Wei Kang Su) Enhances Antioxidant Response in Various Tissues of Rats with Protection Against Carbon Tetrachloride Hepatotoxicity

Wei Kang Su (WKS) is a commercial herbal product based on a Chinese herbal formula, Shengmai San. Here, we investigated the effects of long-term treatment with WKS on mitochondrial antioxidant status and functional ability, as well as heat shock protein (Hsp) 25/70 production, in various tissues of rats. WKS treatment enhanced mitochondrial antioxidant status and ATP generation capacity, as well as Hsp 25/70 production in various rat tissues. WKS treatment suppressed plasma reactive oxygen metabolite levels and protected against carbon tetrachloride hepatotoxicity in rats. Long-term WKS treatment may prevent diseases by enhancing the resistance of mitochondria to oxidative stress.

Protection of Regenerating Liver After Partial Hepatectomy from Carbon Tetrachloride Hepatotoxicity in Rats: Roles of Mitochondrial Uncoupling Protein 2 and ATP Stores

Uncoupling protein 2 (UCP(2)), an inner mitochondrial membrane protein, can limit the generation of reactive oxygen species (ROS) and protect cells from injuries mediated by oxidative stress. We investigated the effect of upregulation of UCP(2) in the regenerating liver 96 h after 68% partial hepatectomy (PH) on the self-protection of regenerating liver against carbon tetrachloride (CCl(4)) poisoning. Hepatotoxicity was induced in vivo by administering CCl(4) to rats that had undergone PH. After CCl(4) poisoning, the regenerating liver appeared to have less histological damage and lower serum alanine aminotransferase (ALT) levels. Lower malondialdehyde production and higher glutathione contents were also observed in the regenerating liver compared with the sham-operated liver after CCl(4) poisoning. UCP(2) expression was markedly elevated in the regenerating liver, and further increased after CCl(4) intoxication. Mitochondrial membrane potential and adenosine triphosphate stores maintained higher levels in the regenerating liver than in sham-operated liver after CCl(4) intoxication. The results showed that the regenerating liver exhibited a potent ability to resist CCl(4) intoxication, and the autoprotection of regenerating liver might result from reduction of ROS by UCP(2) and maintenance of higher ATP stores.

Protective effects of N‐acetyl‐L‐cysteine against acute carbon tetrachloride hepatotoxicity in rats

In recent years, N-acetyl-L-cysteine (NAC) has been widely investigated as a potentially useful protective and antioxidative agent to be applied in many pathological states. The aim of the present work was further evaluation of the mechanisms of the NAC protective effect under carbon tetrachloride-induced acute liver injuries in rats. The rat treatment with CCl4 (4 g/kg, intragastrically) caused pronounced hepatolysis observed as an increase in blood plasma bilirubin levels and hepatic enzyme activities, which agreed with numerous previous observations. The rat intoxication was accompanied by an enhancement of membrane lipid peroxidation (1.4-fold) and protein oxidative damage (protein carbonyl group and mixed protein-glutathione disulphide formations) in the rat liver. The levels of nitric oxide in blood plasma and liver tissue significantly increased (5.3- and 1.5-fold, respectively) as blood plasma triacylglycerols decreased (1.6-fold). The NAC administration to control and intoxicated animals (three times at doses of 150 mg/kg) elevated low-molecular-weight thiols in the liver. The NAC administration under CCl4-induced intoxication prevented oxidative damage of liver cells, decreased membrane lipid peroxidation, protein carbonyls and mixed protein-glutathione disulphides formation, and partially normalized plasma triacylglycerols. At the same time the NAC treatment of intoxicated animals did not produce a marked decrease of the elevated levels of blood plasma ALT and AST activities and bilirubin. The in vitro exposure of human red blood cells to NAC increased the cellular low-molecular-weight thiol levels and retarded tert-butylhydroperoxide-induced cellular thiol depletion and membrane lipid peroxidation as well as effectively inhibited hypochlorous acid-induced erythrocyte lysis. Thus, NAC can replenish non-protein cellular thiols and protect membrane lipids and proteins due to its direct radical-scavenging properties, but it did not attenuate hepatotoxicity in the acute rat CCl4-intoxication model.

Protective effects of melatonin against carbon tetrachloride hepatotoxicity in rats

Melatonin is an indolamine, mainly secreted by the pineal gland into the blood of mammalian species. The potential for protective effects of melatonin on carbon tetrachloride (CCl(4))-induced acute liver injury in rats was investigated in this work. CCl(4) exerts its toxic effects by generation of free radicals; it was intragastrically administered to male Wistar rats (4 g kg(-1) body weight) at 20 h before the animals were decapitated. Melatonin (15 mg kg(-1) body weight) was administered intraperitoneally three times: 30 min before and at 2 and 4 h after CCl(4) injection. Rats injected with CCl(4) alone showed significant lipid and hydropic dystrophy of the liver, massive necrosis of hepatocytes, marked increases in free and conjugated bilirubin levels, elevation of hepatic enzymes (alanine aminotransferase and aspartate aminotransferase) in plasma, as well as NO accumulation in liver and in blood. Melatonin administered at a pharmacological dose diminished the toxic effects of CCl(4). Thus it decreased both the structural and functional injury of hepatocytes and clearly exerted hepatoprotective effects. Melatonin administration also reduced CCl(4)-induced NO generation. These findings suggest that the effect of melatonin on CCl(4)-induced acute liver injury depends on the antioxidant action of melatonin.

Protection of regenerating liver after partial hepatectomy from carbon tetrachloride hepatotoxicity in rats: role of hepatic stimulator substance.

In the present study, we examined the effect of hepatic stimulator substance (HSS) on modulating hepatotoxicity induced by carbon tetrachloride (CCl4) in the regenerating rat liver. Hepatotoxicity was induced in vivo by administering CCl4 to rats that had undergone a 68% partial hepatectomy (PH). In vitro studies were also performed in hepatocytes isolated from PH rats. Hepatic stimulator substance was extracted from regenerating rat liver 96 h after PH and its activity, as determined according to the method of LaBrecque, reached its maximum 96 h after PH. At this time, the mortality induced by CCl4 was significantly decreased in PH rats compared with sham-operated rats (18 vs 59%, P < 0.01). Likewise, changes in serum alanine aminotransferase (ALT) or bilirubin induced by CCl4 were less in rats after 96 h PH. The resistance of regenerating hepatocytes to CCl4 was retained in in vitro samples. Thus, leakage of intracellular ALT or aspartate aminotransferase induced by CCl4 in hepatocytes from 96 h hepatectomised rats was less than in control hepatocytes. HSS demonstrated a protective effect on hepatocytes against CCl4 both in vivo and in vitro. In additional studies, regenerating liver showed increased mitochondrial respiratory activity and enhanced plasma membrane fluidity. The HSS was also shown to increase hepatic mitochondrial respiratory activity and enhance plasma membrane fluidity. Further, the protective effect induced by HSS was correlated with the restoration of mitochondrial respiratory activity and plasma membrane fluidity induced by CCl4. Regenerating rat liver exhibits resistance to CCl4-induced hepatotoxicity, and the protection afforded by the regenerating state can be attributed, at least in part, to HSS-induced increases in mitochondrial respiratory activity and plasma membrane fluidity.

Structure and hepatoprotective activity of a biflavonoid from Canarium manii.

Canarium manii (Burseraceae) was chemically investigated and the presence of the biflavonoid agathisflavone is reported for the first time from this plant. Pharmacologically, this biflavonoid in doses 50.0 mg and 100.0 mg given orally exhibited dose-dependent hepatoprotective activity against experimentally-induced carbon tetrachloride-hepatotoxicity in rats and mice.

Boerhaavia diffusa: A study of its hepatoprotective activity

An alcoholic extract of whole plant Boerhaavia diffusa given orally exhibited hepatoprotective activity against experimentally induced carbon tetrachloride hepatotoxicity in rats and mice. The extract also produced an increase in normal bile flow in rats suggesting a strong choleretic activity. The extract does not show any signs of toxicity up to an oral dose of 2 g/kg in mice.

Hepatotoxicity of carbon tetrachloride after chronic ethanol consumption

Hepatotoxicity of carbon tetrachloride after chronic ethanol consumption was examined in rats fed a standard pellet diet and a 5 or 20% ethanol solution as a sole source of fluid for 1–100 weeks. Carbon tetrachloride hepatotoxicity in rats fed 5 and 20% ethanol (4.0 and 8.8 g of ethanol/kg body weight, respectively) for 1–100 weeks was markedly greater than that in control rats given water instead of ethanol, and the hepatotoxicity in rats fed 20% ethanol was more severe as compared with that in rats fed 5% ethanol at any time during a period of 100 weeks. The degree of the enhanced hepatotoxicity in rats fed both 5 and 20% ethanol did not change significantly during a period of 100 weeks. Moreover, the enhanced hepatotoxicity in the rats fed both 5 and 20% ethanol for 1–100 weeks is of the same degree as that in the rats that received 4.0 and 8.8 g of ethanol/kg body weight as a single dose, respectively. These experimental findings suggest that the effect of ethanol on the carbon tetrachloride hepatotoxicity is dependent on the daily amount of alcohol intake and is not affected by the duration of alcohol consumption.

Potentiation of carbon tetrachloride hepatotoxicity in rats by pretreatment with polychlorinated biphenyls

Pretreatment of male rats with Aroclor 1254 at a dose of 25 mg/kg i.p. for 6 days resulted in potentiation of the hepatotoxicity of inhaled carbon tetrachloride (CCl 4) as evidenced by a decrease in liver glucose-6-phosphase and elevations of serum glutamic oxalacetic transaminace (SGOT), serum glutamic pyruvic transaminase (SGPT), isocitrate dehydrogenase, and sorbitol dehydrogenase. Aroclor 1254 alone did not demonstrate hepatotoxicity. Aroclor 1254 administration resulted in large increases in cytochrome c reductase, cytochrome P-450 (448) and p-nitroanisole demethylation. Subsequent exposure to CCl 4 vapor resulted in over 70% decreases in the latter two parameters. The potentiation was dose-dependent with a dose of 5 mg/kg or higher being effective. Aroclor 1260 administration gave results similar to those of Aroclor 1254, but Aroclor 1221 enhanced CCl 4 toxicity to a lesser extent.

Effect of phenobarbital or pregnenolone-16α-carbonitrile (PCN) pretreatment on acute carbon tetrachloride hepatotoxicity in rats

In rats, CCl 4 hepatotoxicity (reflected by augmented serum glutamic-pyruvic transaminase activity and hepatic triglyceride content) was diminished by pregnenolone-16α-carbonitrile (PCN) and markedly increased by phenobarbital. PCN, like penobarbital, caused smooth-surfaced endoplasmic reticulum proliferation in hepatocytes and enhanced hexobarbital oxidation, ethylmorphine N-demethylation, cytochrome P-450 and NADPH-cytochrome c reductase activity. Contrary to earlier views, it is concluded that the increase in these parameters is not a prerequisite for augmented CCl 4 toxicity. Perhaps the cytochrome P-450 induced by the steroid and barbiturate has different catalytic properties, which are responsible for variations in the response to CCl 4.