CCl4-induced damage to endoplasmatic reticulum membranes

Cytochrome P-450 can be used to indicate damage of the membranes of endoplasmatic reticulum by CCl₄. Free radicals are formed during the metabolism of CCl₄, which stimulate peroxidation of unsaturated fatty acids and directly inactivate cytochrome P-450. The first indication of cytochrome P-450 inactivation is a decrease in the reduction rate in the NADPH-specific electron transfer chain. In microsomes obtained from the liver of poisoned animals NADPH-cytochrome P-450 reductase is not stimulated by DMA.     

Fucoidan partly prevents CCl4-induced liver fibrosis

Fucoidan, a sulfated polysaccharide extracted from brown algae, has a wide range of biological activities, including anti-inflammatory, anti-viral, and anti-tumor activities. In the present study, we investigated the effects of fucoidan on CCl₄-induced liver fibrosis. Administration of fucoidan reduced CCl₄-induced acute and chronic liver failure. Hepatic fibrosis induced by CCl₄ was also attenuated by injection of fucoidan. Damage to hepatocytes and activation of hepatic stellate cells are key events in liver fibrosis, and, interestingly, treatment of hepatocytes with fucoidan prevented CCl₄-induced cell death and inhibited the proliferation hepatic stellate cells. These results indicate that fucoidan might be a promising anti-fibrotic agent possessing dual functions, namely, protection of hepatocytes and inhibition of hepatic stellate cell proliferation.     

软肝片抗肝纤维化作用的实验研究

目的探讨软肝片对四氯化碳中毒性肝纤维化的防治作用。方法用四氯化碳皮下注射造成大鼠肝纤维化模型 ,以联苯双酯作为阳性对照 ,测定血清丙氨酸氨基转移酶 (ALT)、天冬氨酸氨基转移酶 (AST)、玻璃酸(HA)、唾液酸及肝组织羟脯氨酸 (Hyp)、丙二醛 (MDA)、超氧化物歧化酶 (SOD)含量 ,以反映肝细胞损伤及肝纤维化程度。结果软肝片可明显降低肝纤维化大鼠血清ALT、AST、HA、唾液酸水平及肝组织Hyp和MDA水平 ,提高肝组织中SOD活力。结论软肝片具有一定的抗肝纤维化及抗脂质过氧化作用。     

阿魏酸乙酯减轻四氯化碳致小鼠急性肝损伤

阿魏酸(ferulic acid, AF)是桂皮酸的衍生物之一, 普遍存在于当归、川芎等常用中药中[1,2].文献报道其具有抑制血栓形成、调节免疫功能、清除和抑制氧自由基等作用[3].     

Methyl palmitate prevents CCl(4)-induced liver fibrosis

Liver fibrosis is characterized by an excess of collagen fiber deposition, and it is known that Kupffer cells play an important role by immunomodulation of the toxic response. Methyl palmitate (MP) is an effective Kupffer cell inhibitor. The aim of this work was to evaluate the effect of MP on experimental liver fibrosis. Four groups were formed: the control group, which received the vehicles only; CCl(4) group (0.4 g kg(-1), i.p., three times a week, for eight weeks); CCl(4) plus MP (300 mg kg(-1), i.p., daily); and MP alone. Alanine aminotransferase was increased by CCl(4), and MP did not prevent this increase. Lipid peroxidation was increased markedly by CCl(4); again, MP was not able to prevent this effect. Fibrosis increased nearly 6-fold (measured as liver hydroxyproline content) in the CCl(4) group; MP preserved the normal content of collagen. These results were corroborated by histopathology. To elucidate the antifibrogenic mechanism of MP, we measured the production of TGF-beta; CCl(4) increased this cytokine several-fold, and MP abolished this increase. Collectively the present results indicate that MP possesses a strong antifibrogenic effect at least in the CCl(4) model of fibrosis. The antifibrotic effect of MP is probably associated with its ability to reduce TGF-beta content, maybe by immunomodulation of Kupffer cells functioning.     

Potentiation of CCl4-induced liver injury by ketonic and ketogenic compounds: role of the CCl4 dose

Potentiation of haloalkane hepatotoxicity by ketones and ketogenic agents is a well-known phenomenon. The importance of the CCl4 dosage in these combinations, however, has not been explored. Its influence was investigated in male Sprague-Dawley rats. Dose-effect curves for potentiation were generated using 1,3-butanediol, methyl n-butyl ketone or methyl isobutyl ketone as potentiation agents. Animals were orally treated with these compounds prior to a challenge of CCl4 (0 to 0.5 ml/kg, ip). Liver injury was assessed by monitoring plasma ALT activity and bilirubin concentrations after CCl4 treatment. The minimal effective dosage (MED) for each potentiator was used as the criterion of comparison for each combination. The MED values were determined from the plasma ALT data. Results showed that when the CCl4 dosage was increased from 0.01 to 0.10 ml/kg, the MED of each potentiator decreased 10-fold. For a given potentiator, the product of the CCl4 dosage (H, "hepatotoxicant") by the corresponding MED value (P, "potentiator") remained the same in this range of CCL4 dosages. The severity of the liver injury was similar. These findings suggest that a given level of liver injury induced by a ketone/haloalkane combination could be evaluated on the basis of the [P X H] product.     

Hepatoprotection by Elephantopus scaber Linn. in CCl4-induced liver injury

The efficacy of the medicinal plant Elephantopus scaber Linn. (Asteraceae), to prevent carbon teterachloride (CCI4)-induced chronic liver dysfunction in the rats was examined by determining different biochemical markers in serum and tissues. In serum, liver function marker enzymes like aspartate aminotrasferase (AST), alanine aminotrasferase (ALT), alkaline phosphatase (ALP) and also protein were evaluated. The concentrations of total lipid, cholesterol and phospholipids were studied in serum and the different tissues. The concentration of serum triglycerides was also studied. The biochemical changes induced by CCI4 in different tissues particularly in the liver tissue improved following treatment with E. scaber Linn. The results suggest the hepatoprotective effect of this medicinal plant.     

Agaricus blazei Murill extract abrogates CCl4-induced liver injury in rats

Agaricus blazei Murill (ABM) is enriched with polysaccharides, lipids, vitamins, fibers and minerals. Many studies have shown that ABM possesses immune-enhancing and anti-tumor effects. However, little is known about its protective effects on liver function. We employed carbon tetrachloride (CCl(4)) to induce hepatic fibrosis in a rat model to examine the protective effects of ABM on the liver in this study. The experiments included non-treatment control, CCl(4)-only control, and treatment with 200 mg and 2,000 mg of ABM extracts (per kilogram rat weight). All groups other than the non-treatment control were treated with intraperitoneal injections of CCl(4) twice a week. Experimental and control rats were tube-fed with experimental ABM extracts or double-distilled water, respectively, on the remaining four days each week. The whole experimental protocol lasted 8 weeks; blood and liver samples were collected for biochemical and tissue histochemical analysis. Plasma alanine aminotransferase and aspartate aminotransferase, and the activities of the anti-oxidative enzymes glutathione peroxidase, superoxide dismutase and catalase in the liver were measured. We found that high-dose ABM treatment reduced hepatic necrosis and fibrosis caused by CCl(4) in comparison with the CCl(4) control group. ALT and AST activities in the sera collected from ABM-treated rats were lower than those in the CCl(4) control rats. These results suggested that ABM extract was capable of either enhancing liver recovering from CCl(4) damage or attenuating CCl(4) toxicity. Results of anti-oxidative enzyme activity analysis showed no apparent differences among ABM-treated groups and CCl(4) control groups, indicating that removal of free radicals does not explain the protective/recovery effects observed in this study.     

Protective effect of wedelolactone against CCl4-induced acute liver injury in mice

Eclipta, a traditional Chinese medicine, has been used to treat liver disease for centuries. However, the chemical basis and biological mechanisms of Eclipta remain elusive. The current study aims to investigate the hepatoprotective effect of wedelolactone (WEL), a major coumarin in Eclipta, using C57BL/6 mice with carbon tetrachloride CCl₄-induced acute liver injury (ALI). Our data showed that WEL markedly decreased the CCl₄-induced elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and improved hepatic histopathology changes. WEL also significantly decreased the content of MDA in liver tissues, meanwhile increased the activities of antioxidant enzymes SOD and GSH-Px. In addition, WEL reduced the protein expression of TNF-α, IL-1β and IL-6, as well as mRNA expression. Western blot results revealed that WEL repressed phosphorylation of extracellular signal-regulated kinase (ERK) and translocation of NF-κB p65 from cytoplasm to nucleus and enhanced the phosphorylation of c-Jun. N-terminal kinase (JNK). Moreover, results showed that WEL significantly inhibited CCl₄-induced hepatocytes apoptosis, markedly suppressed the down-regulation of Bax and active Caspase-3 expression and accelerated the expression of Bcl-2. Overall, the findings indicate that WEL exhibits a protective effect against CCl₄-induced ALI in mice by enhancing the antioxidative defense system, suppressing the inflammatory response and cell apoptosis of liver.     

Change of drug excretory pathway by CCl4-induced liver dysfunction in rat

Liver dysfunction affects the pharmacokinetics of drugs. The liver plays an important role in drug excretion as well as drug metabolism and pharmacokinetics. In the present study, the relationship between changes in the cefmetazole (CMZ) excretory pathway and the degree of liver dysfunction induced by CCl(4) treatment was investigated. CMZ is mainly excreted as an unchanged form in feces in control rats. Depending on the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), urinary CMZ excretion was increased, whereas fecal CMZ excretion was decreased in rat with liver dysfunction. The AUC of CMZ in rats with severe liver dysfunction was approximately 2-fold higher than that in control rats. Since drug transporters could be involved in drug excretion, changes in the expression of representative hepatic drug transporters in liver dysfunction were investigated by rat DNA microarray. Basolateral solute carrier transporters such as Ntcp, Oct1, and Oatp2 were decreased and basolateral ATP-binding cassette transporters such as Mrp3 and Mrp4 were increased by the CCl(4) treatment. On the other hand, canalicular Mrp2 and Bsep were decreased, but Mdr1 was increased. However, the transporter system for CMZ has not been identified yet. In conclusion, we clarified that the fecal and urinary excretory profiles of CMZ were changed clearly depending on the serum AST and ALT levels in liver dysfunction. The changes in the CMZ excretory pathway might be responsible for the changes in the expression of drug transporters.     

网状五层龙热水提取物对小鼠急性肝损伤的保护作用

网状五层龙(salacia reticulata)产于斯里兰卡和印度的南部,自古以来便被当地人们作为草药来防治一些疾病,民间常用于保肝、风湿病、镇痛、皮肤病、淋病、闭经、抗炎和糖尿病等[1,2],近年还发现网状五层龙根、茎部提取物中含有可竞争抑制小肠黏膜刷状缘内α-葡糖苷酶的抑制剂,从而延迟蔗糖、麦芽糖和淀粉等多糖分解为单糖并经肠道吸收,降低餐后高血糖和缓解胰高血糖症[3]。但是网状五层龙其他的传统作用还没有得到科学证实,为此我们采用网状五层龙热水提取物(hot water extract fromSalacia reticulata,SRHW)对四氯化碳(CCl4)所致小鼠急…     

Hepatoprotection of emodin and Polygonum multiflorum against CCl4-induced liver injury

Context: Polygonum multiflorum is known as a medicinal plant. It has been used as a folk medicine which showed antioxidative property.

Objective: Protective effects of the water extracts (w/v:1/10) from fresh P. multiflorum (WEP) on carbon tetrachloride (CCl₄)-induced liver damage in rats were investigated.

Materials and methods: CCl₄ was used for inducing liver damage of SD rats, and WEP and emodin were fed for eight consecutive weeks.

Results: We found that emodin levels in fresh WEP was higher than that in ripening WEP. Rats were administered WEP and emodin, the main active compound, for 56 consecutive days. WEP significantly lowered the serum levels of hepatic enzyme markers, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and reduced the generation of malonaldehyde. Treatment with WEP recovered glutathione S-transferase and catalase activity in rats as compared to treatment with CCl₄ alone. In addition, serum tumor necrosis factor-α, an inflammatory marker, was found to decrease in rats treated with WEP. In histopathological evaluation, fatty degeneration and necrosis were found to be significantly decreased in the CCl₄ plus WEP treatment group.

Discussion and conclusion: WEP may be effective in attenuating liver damage by reducing lipid peroxidation as well as by positively modulating inflammation.     

虎杖提取物对CCl4诱导的小鼠急性肝损伤的保护作用

目的观察虎杖提取物对CCl4诱导的小鼠急性肝损伤的保护作用。方法采用CCl4诱导小鼠急性肝损伤模型,测定血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、肝组织超氧化物歧化酶（SOD）活性及丙二醛（MDA）含量。结果 CCl4诱导的小鼠急性肝损伤模型,血清ALT、AST明显升高,肝组织SOD活性明显降低,MDA含量显著升高（P〈0.01）;虎杖提取物能显著降低血清ALT,AST,明显提高肝组织SOD活性,降低肝组织MDA含量（P〈0.01）。结论虎杖提取物具有降酶及抗氧化的作用,对CCl4诱导的小鼠急性肝损伤具有一定的保护作用。     

虎杖提取物对小鼠急性肝损伤的保护作用

目的观察虎杖提取物对cch诱导的小鼠急性肝损伤的保护作用。方法采用CCl4诱导小鼠急性肝损伤模型,测定血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AsT）、肝组织超氧化物歧化酶（S（）D）活性及丙二醛（MDA）含量。结果cch诱导的小鼠急性肝损伤摸型,血清ALT、AST明显升高,肝组织SOD活性明显降低,MDA含量显著升高（P〈0．01）;虎杖提取物能显著降低血清ALT,AST,明显提高肝组织SOD活性,降低肝组织MDA含量（P〈0．01）。结论虎杖提取物具有降酶及抗氧化的作用。对CCh诱导的小鼠急性肝损伤具有一定的保护作用。     

Hepatoprotective activity of Stereospermum suaveolens against CCl4-induced liver damage in albino rats

The present study aims to evaluate the hepatoprotective activity of Stereospermum suaveolens DC (Bignoniaceae). Hepatoprotective activity is studied by carbon tetrachloride (CCl₄)-induced liver damage in albino rats. The degree of protection in this activity has been measured by using biochemical parameters such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, LDL-cholesterol and SOD, CAT, GSH, total thiols, NO, and lipid peroxidation in liver tissue homogenate. The results suggest that the methanol stem bark extract of Stereospermum suaveolens at the doses 125, 250, and 500?mg/kg and reference standard Liv-52 treated group produced significant (p <0.001) hepatoprotection against CCl₄-induced liver damage by decreasing the activities of serum enzymes, bilirubin and lipid peroxidation. The extract significantly (p <0.001) increased levels of SOD, CAT, GSH and total thiols, as compared to control group. Histopathological studies further substantiate the protective effect of the extract. It was concluded that methanol stem bark extract of Stereospermum suaveolens showed effective hepatoprotective activity.     

黄芩素对四氯化碳诱导小鼠急性肝损伤的保护作用

<正>黄芩素是一种天然类黄酮物质,提取于唇形科植物高黄芩(Scutellaria altissima L.)的全草中,因其抗炎、解热作用[1]显著、毒副作用小越来越多的受到人们的重视。本实验室首次通过灌胃黄芩素并采用四氯化碳诱导急性肝损伤小鼠模型,观察黄芩素对肝脏的影响并讨论了其可能的作用机制。1材料与方法1.1材料及仪器健康昆明小鼠(♂),体质量18～22 g,清洁级,由第四军医大学动物实验中心提供。黄芩素(中国食     

阿魏酸钠的抗肝损伤作用及其机制研究

目的 :研究阿魏酸钠 (SF)的抗CCl4肝损伤作用及其作用机制。方法 :以血清ALT、AST为诊断指标 ,建立急性肝损伤模型 ,测定肝细胞浆抗氧化酶、肝线粒体ATP酶和膜流动性。结果 :CCl4致小鼠血清ALT和AST升高时 ,单胺氧化酶显著升高 ,过氧化氢酶、谷胱甘肽S 转移酶 (GST)及膜荧光偏振度、平均微粘度显著降低 ,Na ,K ATP酶、Ca2 ,Mg2 ATP酶活性呈降低趋势。预先给予SF 5 0～15 0mg·kg-1(ip ,qd× 9)后能明显逆转上述改变 ,并呈剂量依赖性变化。结论 :SF对CCl4肝损伤有保护作用。其作用机制除抑制脂质过氧化作用外 ,还与增强肝GSH结合功能 ,保护线粒体膜结构和功能有关。     

甘草酸对四氯化碳致小鼠肝纤维化及骨丢失的防治作用

目的　研究甘草酸对肝纤维化小鼠骨丢失的防治作用。方法　用体积分数为 4 0 %的CCl4花生油皮sc 5wk致小鼠肝纤维化 ,观察与肝损伤相关的各种生化指标和肝脏病理切片结果以及测定小鼠右股骨的骨Ca2 + 量和其他骨微量元素以及骨羟脯胺酸的含量。结果　单用CCl4小鼠呈现典型的慢性肝损伤后肝纤维化的改变 ,骨重量和骨钙总量及骨羟脯胺酸的含量减少 (P <0 0 5 ) ,而甘草酸治疗组有明显的护肝及对抗骨丢失作用。结论　甘草酸在所用的剂量下对肝纤维化及骨丢失有一定预防作用     

Modulation of the course of CCl4-induced liver injury by the anti-calmodulin drug thioridazine

Thioridazine (TDZ) administration to rats (50 mg/kg i.p.) 6 or 10 h after CCl4 treatment (1 ml/kg in olive oil i.p.) partially prevented necrogenic effects of this compound at 24 h but not at 72 h. TDZ did not have inhibitory effects on CCl4 activation, covalent binding (CB) of reactive metabolites to cellular constituents or CCl4-induced lipid peroxidation (LP). Moreover, TDZ had enhancing effects on both LP and CB. TDZ was able to increase protein and phospholipid synthesis and slightly but significantly enhanced protein but not phospholipid degradation in livers from control rats. TDZ administration decreased calcium liver content in CCl4-poisoned animals but did not change the intensity of CCl4-induced fatty liver. TDZ lowered body temperature in CCl4-treated animals during the 24 h observation period. These results and previous studies from our laboratory suggest calcium and calmodulin (CaM) participation in the CCl4 necrogenic effects on the liver but not in the hepatotoxin-induced fatty liver. TDZ-lowering effects on body temperature might also be a determinant in the delaying effects of this drug on the onset of CCl4-induced necrosis. Present experiments did allow discrimination between these two or other possible mechanisms for TDZ modulation effects.     

Phenobarbital pretreatment alters the localization of CCl4-induced changes in rat liver microsomal fatty acids

Phenobarbital treatment induces an isozyme(s) of liver microsomal cytochrome P450 susceptible to CCl4 and enhances the latter's lethality. We have now studied phenobarbital's effect on the specificity of phosphatidyl fatty acid changes in rat liver microsomes. Male Sprague-Dawley rats were pretreated with three daily ip doses of phenobarbital (50 mg/kg) or saline and then orally dosed with CCl4 (2.5 ml/kg). Liver microsomes were prepared 7.5 to 180 min after CCl4 treatment, the lipid fraction was extracted, diene conjugate content was determined, and phospholipids were separated by HPLC for fatty acid content determination. Protein, phospholipid, and phosphatidyl fatty acid residue loss occurred early (7.5 to 30 min) and in some cases later (60 to 180 min) in both pretreated groups, suggesting that two phases of CCl4-mediated injury occurred. Phenobarbital pretreatment accelerated the CCl4-induced formation of diene conjugates in the microsomal lipids. In studies on the separated phospholipids, phenobarbital alone altered microsomal fatty acid content, primarily decreasing arachidonic acid in favor of linoleate, particularly in phosphatidylserine. During the early phase of CCl4 injury, phenobarbital pretreatment shifted the major loss of arachidonic acid from phosphatidylserine to phosphatidylethanolamine. During the later phase, arachidonic acid loss was still prominent, but the most extensive CCl4-induced changes in fatty acids occurred in the neutral lipid fraction, regardless of pretreatment. These changes included loss of neutral lipid linoleic and docosahexanoic acids associated with an increase in palmitic acid. These data demonstrate that phenobarbital pretreatment is associated with a shift in the predominant phospholipid locus from phosphatidylserine to phosphatidylethanolamine for the early CCl4-induced fatty acid changes in rat liver microsomes.