Agonistic antibodies to Fas induce a breach in the endothelial lining of the liver and a breakdown in B cell tolerance

Liver disease can be associated with a breakdown in self-tolerance and the production of autoantibodies such as rheumatoid factors (RF), which bind to IgG. Here we investigated whether primary, non-infectious liver damage was sufficient to induce autoantibody production. We established a model of targeted liver damage induced by weekly sublethal injections of pro-apoptotic anti-Fas (CD95) antibodies. Liver damage, monitored by measurements of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, was minimal 1 week after anti-Fas injection. However, the sublethal Fas stimulation was sufficient to trigger significant haemorrhage in the liver, as assessed by Evans Blue dye leakage into the organ 5 h after anti-Fas antibody injection. We observed an induction of RF in response to the weekly injections of sublethal anti-Fas antibodies but not of isotype control antibodies, indicating a breakdown of self-tolerance induced by Fas engagement. RF induction was unlikely to be due to direct activation of B cells, as splenocytes stimulated with anti-Fas antibodies in vitro did not produce RF. These studies show that sublethal damage to the liver by Fas engagement leads to liver haemorrhage and is sufficient to trigger the breakdown of self-tolerance.     

Hepatoprotective effect of the natural fruit juice from Aronia melanocarpa on carbon tetrachloride-induced acute liver damage in rats.

The fruits of Aronia melanocarpa are rich in anthocyanins--plant pigments with anti-inflammatory and antioxidant activity. We studied the effect of the natural fruit juice from A. melanocarpa (NFJAM) on carbon tetrachloride (CCl4)-induced acute liver damage in rats. Histopathological changes such as necrosis, fatty change, ballooning degeneration and inflammatory infiltration of lymphocytes around the central veins occurred in rats following acute exposure to CCl4 (0.2 ml kg(-1), 2 days). The administration of CCl4 increased plasma aspartate transaminase (AST) and alanine transaminase (ALT) activities, induced lipid peroxidation (as measured by malondialdehyde (MDA) content in rat liver and plasma) and caused a depletion of liver reduced glutathione (GSH). NFJAM (5, 10 and 20 ml kg(-1), 4 days) dose-dependently reduced the necrotic changes in rat liver and inhibited the increase of plasma AST and ALT activities, induced by CCl4 (0.2ml kg(-1), 3rd and 4th days). NFJAM also prevented the CCl4-induced elevation of MDA formation and depletion of GSH content in rat liver.     

The effect of carbon tetrachloride on the copper-laden rat liver

Copper is believed to be hepatotoxic in Indian Childhood Cirrhosis and Wilson's disease. However, copper-loading causes only minimal hepatic damage in animal models. The hypothesis was therefore proposed that a second hepatic insult may precipitate or perpetuate liver injury in a copper-laden liver. In non-copper-dosed rats CCl4 (10 mmol/kg, i.p.) produced elevated serum AST (809 +/- 298 IU/l, normal 20 +/- 5) and ALT (295 +/- 157 IU/l, normal 6 +/- 1) and extensive liver cell necrosis, portal tract inflammation, fat deposition, and perilobular hepatocyte ballooning. In rats whose liver copper was elevated from 75 +/- 13 to 461 +/- 13 micrograms/g by oral copper supplementation, CCl4 produced much smaller increases in AST (492 +/- 80 IU/l) and ALT (172 +/- 57 IU/l) and mild focal liver cell necrosis. Fat deposition and perilobular vacuolation were not reduced. Prior copper-loading of rats unequivocally protected against the CCl4-induced liver injury. Triglyceride accumulation, however, was apparently unaffected. The possible interactions of copper with prostaglandin-mediated inflammation and with free-radical-induced liver damage are discussed.     

细脚拟青霉多糖对抗四氯化碳诱导的急性肝损伤

目的：观察细脚拟青霉粗多糖（cPtPs）及其纯化多糖（PtPs）对四氯化碳（CCl4）诱导大鼠急性肝坏死的影响。方法：将Wistar大鼠分为4组（对照组、CCl4组、cPtPs +CCl4组和PtPs +CCl4组），分别用生理盐水、cPtPs和PtPs灌胃15 d，最后2 d，腹腔注射CCl4，16 h后全自动生化分析仪检测血清中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、总胆红素（TBIL）、直接胆红素（DBIL）和间接胆红素（IBIL）；肝组织苏木素-伊红（HE）染色观察病变程度；黄嘌呤氧化酶法和硫代巴比妥酸法分别检测肝匀浆中超氧化物歧化酶（SOD）和丙二醛（MDA）；甲基百里香酚蓝比色法测定肝细胞线粒体中Ca2+ 浓度；免疫组织化学法检测肝组织中α-平滑肌肌动蛋白（α-SMA）的表达。结果：与对照组比较，CCl4组血清中ALT、AST、TBIL、DBIL和IBIL的含量显著增加（P＜0.05），HE染色肝组织变性坏死累及全小叶。与CCl4组比较，PtPs+CCl4组血清中ALT、AST、TBIL、DBIL和IBIL的含量显著下降（P＜0.05）；PtPs +CCl4组HE染色病变程度较轻，变性坏死局限于肝小叶的Ⅲ区；PtPs +CCl4组胞浆中SOD活性提高， MDA水平降低（P＜0.05）；PtPs +CCl4组和cPtPs +CCl4组线粒体中Ca2+ 浓度均下降（分别为P＜0.05，P＜0.01）；PtPs +CCl4组α-SMA在肝组织的坏死区几乎无表达。结论：PtPs能显著减轻CCl4诱导的肝损伤，可能与PtPs抗脂质过氧化作用相关，效果优于cPtPs。     

The effect of carbon tetrachloride on the copper-laden rat liver.

Copper is believed to be hepatotoxic in Indian Childhood Cirrhosis and Wilson''s disease. However, copper-loading causes only minimal hepatic damage in animal models. The hypothesis was therefore proposed that a second hepatic insult may precipitate or perpetuate liver injury in a copper-laden liver. In non-copper-dosed rats CCl4 (10 mmol/kg, i.p.) produced elevated serum AST (809 +/- 298 IU/l, normal 20 +/- 5) and ALT (295 +/- 157 IU/l, normal 6 +/- 1) and extensive liver cell necrosis, portal tract inflammation, fat deposition, and perilobular hepatocyte ballooning. In rats whose liver copper was elevated from 75 +/- 13 to 461 +/- 13 micrograms/g by oral copper supplementation, CCl4 produced much smaller increases in AST (492 +/- 80 IU/l) and ALT (172 +/- 57 IU/l) and mild focal liver cell necrosis. Fat deposition and perilobular vacuolation were not reduced. Prior copper-loading of rats unequivocally protected against the CCl4-induced liver injury. Triglyceride accumulation, however, was apparently unaffected. The possible interactions of copper with prostaglandin-mediated inflammation and with free-radical-induced liver damage are discussed.     

Effect of fermented Angelicae gigantis Radix on carbon tetrachloride-induced hepatotoxicity and oxidative stress in rats

This study is aimed to evaluate the protective effect of fermented Angelicae gigantis Radix (AGR) with Monascus purpureus strain on carbon tetrachloride (CCl(4))-induced hepatotoxicity and oxidative stress in rats. The activities of liver marker enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and the levels of lipid peroxidation were increased when CCl(4) was treated but these parameters were significantly decreased by fermented AGR treatment. CCl(4) treatment exhibited decrease in serum concentrations of triglyceride, total cholesterol, HDL-cholesterol, and free fatty acids, and these were also decreased by fermented AGR administration. The level of serum leptin was significantly lower in fermented AGR administration than that in normal control group. CCl(4) treatment significantly increased the concentration of liver triglyceride. The current study observed significant elevations of the thiobarbituric acid-reactive substances (TBARS) levels in the liver homogenate, mitochondrial, and microsomal fractions of CCl(4) control group compared with normal control group. CCl(4) treatment resulted in a significant decrease in the levels of plasma and hepatic glutathione, but these reductions were significantly increased by fermented AGR administration. CCl(4) induced the marked hepatocytes necrosis and fatty accumulation around the central veins. Accordingly, fermented AGR may be an ideal candidate for the hepatoprotective effect in animal model.     

原卟啉钠对急性肝损伤小鼠肝组织SOD、MDA的影响

 目的 探讨原卟啉钠对四氯化碳（CCl4）致急性肝损伤小鼠血清转氨酶和肝组织超氧化物歧化酶（SOD）、脂质过氧化产物丙二醛（MDA）的影响。方法 60只ICR小鼠随机分为正常对照组、CCl4模型组、联苯双酯组、原卟啉钠低、中、高剂量组。各治疗组每天灌胃给药及造模16h后,摘眼球取血测定血清中谷丙转氨酶（ALT）和谷草转氨酶（AST）活性,剖腹取肝测定肝脏SOD活力和MDA含量。结果 CCl4模型组小鼠血清ALT和AST活力分别为（1879±1219）、（2210±1585）U/L,与正常对照组比较,降低显著（P<0.01）;联苯双酯组、原卟啉钠低、中、高剂量组的SOD活力和MDA含量分别为（207.61±16.02）、（184.35±13.42）、（190.88±17.77）、（199.38±14.43）U/mgprot和（1.08±0.15）、（1.35±0.26）、（1.07±0.16）、（0.92±0.18）nmol/mgprot,与CCl4模型组比较,差异有统计学意义（P<0.05～P<0.01）。结论 原卟啉钠能有效阻止CCl4致急性肝损伤小鼠肝组织SOD活性降低,脂质过氧化产物MDA含量升高,具有一定的保肝降酶作用。     

Ameliorating effect of phytoestrogens on CCl4-induced oxidative stress in the livers of male Wistar rats

Glutathione-S-transferases and glutathione play a key role in the detoxification of most toxic agents. In the present study, the protective effects, if any, of isoflavone phytoestrogens--genistein and daidzein on the carbon tetrachloride (CCl4) induced changes in the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione S transferase (GSH) and levels of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS)-were studied. The activities of ALT and AST were assayed in the serum, whereas the activity of GST and levels of GSH and TBARS were determined in the livers of rats. The current study involved the division of animals into two main groups: (i) rats pretreated with genistein and daidzein for three days; and (ii) non-pretreated rats. In the pretreated group, rats received oral doses of genistein (7.9 micromol/kg body weight) and daidzein (7.9 micromol/kg body weight) for three consecutive days (once daily) followed by oral dose of CCl4 on the 4th and the 5th day concurrently with the phytoestrogens-genistein or daidzein. In the non-pretreated group animals received oral dose of CCl4 (1 ml/kg body weight) for two consecutive days along with the phytoestrogens-genistein or daidzein. Treatment of male rats with CCl4 significantly elevated the activity of ALT and AST in serum and levels of TBARS in the liver. On the other hand, CCl4 resulted in decreased activity of GST and lowered the GSH levels. Coadministration of genistein and daidzein with CCl4 could not restore the alterations in the activity of ALT and AST caused by CCl4 to normal control levels. However, repeated dose treatments with genistein and daidzein for three days prior to the administration of CCl4 restored such alterations to normal levels. Our results indicate that genistein is more effective than daidzein in counteracting the inhibition of GST activity caused by CCl4 and restoring it to normal levels. Genistein was also more effective than daidzein restoring the induced TBARS levels caused by CCl4 to normal control levels when rats were pretreated with the isoflavone orally for three days. It has been observed that the tested isoflavonoids were able to antagonize the toxic effects of CCl4. Such counteracting effects were more pronounced for genistein and when the phytoestrogens were administered as repeated doses prior CCl4 administration.     

Inflammatory cytokine response to Vibrio vulnificus elicited by peripheral blood mononuclear cells from chronic alcohol users is associated with biomarkers of cellular oxidative stress

Vibrio vulnificus is the leading cause of death in the United States associated with the consumption of raw seafood, particularly oysters. In epidemiological studies, primary septicemia and inflammation-mediated septic shock caused by V. vulnificus is strongly associated with liver disease, often in the context of chronic alcohol abuse. The present study was undertaken to determine whether clinical biomarkers of liver function or cellular oxidative stress are associated with peripheral blood mononuclear cell inflammatory cytokine responses to V. vulnificus. Levels of interleukin-1 beta (IL-1 beta), IL-6, IL-8, and tumor necrosis factor alpha elicited in response to V. vulnificus and measured in cell supernatants were not associated with the liver biomarkers aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or the AST/ALT ratio. In contrast, reduced glutathione (GSH) levels were associated with the release of all four cytokines (IL-1 beta [R(2) = 0.382; P = 0.006], IL-6 [R(2) = 0.393; P = 0.005], IL-8 [R(2) = 0.487; P = 0.001], and TNF-alpha [R(2) = 0.292; P = 0.021]). Those individuals with below-normal GSH levels produced significantly less proinflammatory cytokines in response to V. vulnificus. We hypothesize that persons with markers for cellular oxidative stress have increased susceptibility to V. vulnificus septicemia.     

PGE2 alleviates kidney and liver damage, decreases plasma renin activity and acute phase response in cirrhotic rats with acute liver damage.

In this study, we evaluated the effect of prostaglandin E2 (PGE2) on renal and hepatic function using an experimental cirrhosis model plus acute liver damage (ALD). Male Wistar rats treated with carbon tetrachloride (CCl4) for 8 weeks were used for the cirrhosis model. Cirrhotic rats were further exposed to an additional acute dose of CCl4 to induce ALD and then treated with PGE2 intramuscularly twice a day for 7 days (200 microg/Kg/day). PGE2 administration started 3 h after the additional dosing of CCl4 and PGE2 effect on hepatorenal function was examined on days 1, 2, 3, and 7. PGE2-treatment ameliorated the decrease in urinary sodium excretion, and normalized serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and plasma renin observed in cirrhotic rats with ALD. In addition, PGE2-treatment decreased mean arterial pressure, glomerular hypercellularity and thickening of the kidney capillary wall, and liver steatosis and cellular necrosis. Also, PGE2 increased the number of regenerative nodules. Finally, PGE2-treatment inhibited the increase in Alpha 1-acid glycoprotein (pAGP), fibrinogen, and Apo A-1 mRNA expression by 83%, 59%, and 77%, respectively. These results suggest that PGE2 administration may decrease the expression of acute phase proteins. In conclusion, PGE2-treatment improved hepatic and renal function and may be useful to down-regulate the acute phase response in cirrhotic rats presenting ALD induced by CCl4.     

Protective effects and antioxidant mechanism of bamboo leaf flavonoids on hepatocytes injured by CCl4

The protective effects and antioxidant mechanisms of bamboo leaf flavonoids (BLFs) on hepatocytes injured by CCl₄ were studied by establishing models of hepatocyte damage induced by CCl₄ and detecting the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione peroxidase (GSH-Px), superoxide dismurase (SOD), malondialdehyde (MDA) content and liver glycogen content. The degree of lesions in liver tissues between model and dosage groups was observed through paraffin sections. Results showed that BLFs significantly inhibit CCl₄-induced liver injury. The ALT and AST activities as well as MDA contents of cells decreased significantly after treatment with BLFs. GSH-Px and SOD activities as well as liver glycogen contents remarkably increased in the flavonoids groups, which exhibited dose-dependent relationships (P < 0.05). The degree of lesions in liver tissues in the BLF groups was microscopically better than that in the model group. BLFs also significantly suppressed hepatocellular injury and death of apoptotic cells. Therefore, BLFs have remarkable protective effects on acute liver injury, which is related to its strong antioxidant capacity to reduce damage in the liver caused by oxidative stress and cell (NCTC-1469) apoptosis. The results of this study provide pharmacological evidence to support the clinical application of BLFs.     

丹参酮IIA对CCl4诱导小鼠急性肝损伤的保护作用

目的 研究丹参酮IIA(tanshinone ⅡA, Tan ⅡA)对CCl4诱导小鼠急性肝损伤的抗氧化、保护作用及其可能的作用机制。 方法 将C57BL/6J小鼠随机分成正常组、CCl4组以及Tan ⅡA保护组(Tan ⅡA 20 mg/kg+CCl4),每组10只。腹腔注射CCl4构建小鼠急性肝损伤模型。计算各组小鼠的肝脏指数,检测血清AST和ALT活性,测定肝组织SOD活性及GSH、MDA含量,HE染色观察肝组织病理变化,免疫组织化学法和Western blot检测肝组织PI3K、p-PI3K、Akt、p-Akt、Nrf2和HO-1蛋白表达水平。 结果 与CCl4组相比,Tan ⅡA保护组肝脏指数显著下降(P<0.01),血清AST(P<0.01)和ALT活性降低(P<0.05),肝组织SOD活性(P<0.01)及GSH含量升高(P<0.05),MDA含量降低(P<0.05),肝组织病理变化得到显著改善。同时,Tan ⅡA使肝组织p-PI3K和p-Akt表达水平明显升高(P<0.01),显著诱导Nrf2转位入核(P<0.01),促使其下游靶蛋白HO-1表达水平明显升高(P<0.01)。 结论 Tan ⅡA能够显著改善CCl4诱导的急性肝损伤,其机制可能与PI3K/Akt/Nrf2/HO-1信号通路有关。     

Prior treatment with captopril attenuates carbon tetrachloride-induced liver injury in mice

The present investigation focused on the possible hepatoprotective potential of captopril on carbon tetrachloride (CCl4)-induced acute liver injury in mice. Twenty-four hours after a single intraperitoneal injection of CCl4 (20 microl/Kg), hepatotoxicity was evidenced in the serum by elevated levels of aspartate transaminase (AST; EC: 2.6.1.1), alanine transaminase (ALT; EC: 2.6.1.2) and lactate dehydrogenase (LDH; EC: 1.1.1.27) and in the liver by depleted level of reduced glutathione (GSH), enhanced activity of glutathione peroxidase (GSH-Px; EC: 1I.11.1.9) and elevated level of lipid peroxides (LP). Captopril was given orally at three dose levels viz., 10, 25 and 50 mg/Kg/day for three consecutive days before subjecting the animals to the hepatotoxin. With the exception of the lowest dose namely, 10 mg/Kg/day, captopril afforded protection against CCl4-induced hepatotoxicity to different extents. Thus, the elevated activities of the enzymes AST, ALT, LDH and GSH-Px as well as the enhanced lipid peroxidation were markedly reduced below those elicited by the hepatotoxin, reaching values closer to the control, though still statistically higher. Captopril, however, did not ameliorate the depletion of GSH produced by CCl4. The data reported herein reveal a protective potential of captopril against the acute hepatotoxicity induced by CCl4 in mice. This hepatoprotection could be attributed, at least in part, to the free radical scavenging properties of the drug.     

Suppression of experimental hepatic fibrosis by administration of vitamin A

The effect of vitamin A on experimental hepatic fibrosis in rats induced by administration of carbon tetrachloride (CCl4) and pig serum was studied. Vitamin A content in the CCl4-induced cirrhotic liver decreased significantly. Administration of pig serum caused hepatic fibrosis without hepatocytic damage. Vitamin A suppressed induction of experimental hepatic fibrosis by CCl4 and pig serum. Neither hepatocytic injury nor increased activities of serum aspartate aminotransferase and glutamic pyruvic transaminase induced by CCl4 was diminished by vitamin A. These data provide evidence that vitamin A inhibits hepatic fibrogenesis and that this effect may be mediated by an action on stellate cells rather than hepatocytes.     

生长抑素及奥曲肽的肝细胞保护作用及其机制研究

目的： 探讨生长抑素（SST）及其类似物奥曲肽（OCT）对大鼠肝细胞的保护作用及其机制。方法: 以原代培养肝细胞建立无水乙醇/四氯化碳（CCl4）细胞损伤模型，观察SST及OCT预处理对培养上清液中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）含量的影响。此外，将75只SD大鼠随机分为正常对照组、肝纤维化模型组及大、中、小剂量SST治疗组。除正常对照组外均以40％CCl4皮下注射8周，期间各SST治疗组分别给予SST 200 μg·kg-1·d-1、100 μg·kg-1·d-1、50 μg·kg-1·d-1。采用酶试剂法、末端核苷酸转移酶介导的脱氧三磷酸尿苷原位缺口末端标记法（TUNEL）分别检测肝功能及肝细胞凋亡指数。结果: 经SST（10-8-10-6 mol/L）及OCT（10-7-10-5 mol/L）预处理后，损伤模型组肝细胞的培养上清液中ALT、AST水平显著下降。不同剂量SST治疗还能明显降低肝纤维化大鼠的血清ALT、AST、碱性磷酸酶（ALP）及总胆红素（TBIL）水平，提高血清清蛋白（ALB）水平，抑制肝细胞凋亡，其中小剂量SST治疗组最佳。结论: SST及OCT可减轻CCl4引起的肝细胞损伤，改善肝功能，并抑制肝细胞凋亡，可能在肝纤维化的防治中发挥重要作用。     

BMP-7 attenuates liver fibrosis via regulation of epidermal growth factor receptor

The aim of this study was to elucidate the effect of bone morphogenetic protein-7 (BMP-7) on liver fibrosis induced by carbon tetrachloride (CCl4) in vivo and on the hepatic stellate cells (HSC) activation in vitro. In vivo, thirty male ICR mice were randomly allocated to three groups, the control group (n = 6), the CCl4 group (n = 18) and the BMP-7+CCl4 group (n = 6). The model of liver fibrosis was induced by intraperitoneal injection with CCl4 three times per week lasting for 12 weeks in CCl4 group and the BMP-7+CCl4 group. After 8 weeks injection with CCl4, mice were intraperitoneal injected with human recombinant BMP-7 in BMP-7+CCl4 group. Meanwhile, mice in the CCl4 group were only intraperitoneal injection with equal amount of saline. The degree of liver fibrosis was assessed by HE and Masson’s staining. PCR and western blot were used to detect mRNA and protein levels. In BMP-7+CCl4 group, serum levels of alanine aminotransferase (ALT) and aminotransferase (AST) were decreased and serum albumin (Alb) was increased. Meanwhile, the expressions of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) were down-regulated by BMP-7 intervention as compared to the CCl4 group (P < 0.05). Furthermore, BMP-7 also suppressed the expression of epidermal growth factor receptor (EGFR) and phosphorylated-epidermal growth factor receptor (pEGFR). HE and Masson stain showed that liver damage was alleviated in BMP-7+CCl4 group. In vitro study, expression of EGFR, TGF-β1 and α-SMA were down regulated by BMP-7 dose-dependently, indicating it might effect on suppression of HSC activation. Therefore, our data indicate BMP-7 was capable of inhibiting liver fibrosis and suppressing HSCs activation, and these effects might rely on its crosstalk with EGFR and TGF-β1. We suggest that BMP-7 may be a potential reagentfor the prevention and treatment of liver fibrosis.     

重组白介素-1受体拮抗剂对实验性肝损伤保护作用的初步研究

白介素１（ＩＬ１） 是重要的炎症因子之一, 在肝损伤中起着重要的作用。为研究重组ＩＬ１ 受体拮抗剂ｒＩＬ１ｒａ） 对四氯化碳（ＣＣＩ４） 诱导的肝损伤的保护作用,将２４ 只Ｗｉｓｔａｒ 大鼠随机分为５ 组：即正常对照组（ｎ ＝ ５） ,造模组（ｎ ＝ ５） ,ｒＩＬ１ｒａ 高剂量（０ ．５ ｍ ｇ／１００ ｇ） 组（ｎ ＝ ５） ,中剂量（０ ．２ ｍｇ／１００ ｇ） 组（ｎ ＝ ５） 和低剂量（ｏ ．１ｍ ｇ／１００ ｇ） 组（ｎ ＝ ４） 。检测处理６ 周末血清肝酶学（ＡＬＴ,ＡＳＴ） 和肝纤维化指标：Ⅲ型前胶原（Ｐｃ Ⅲ） 、透明质酸（ ＨＡ） 和层粘蛋白（ＬＮ） 。结果：与造模组相比较,ｒＩＬ１ｒａ 各剂量组血清ＡＬＴ 和ＡＳＴ 的水平下降（ Ｐ ＜ ０ ．００１ 和Ｐ ＜ ０ ．０１） ,但组间无差异;而对于肝纤维化指标,虽然数值有下降趋势,但只有高剂量才具有统计学意义（ Ｐ ＜ ０ ．０５） 。表明ｒＩＬ１ｒａ（０ ．５ｍ ｇ／１００ ｇ） 可阻断肝细胞的急、慢性损伤,抑制肝纤维化的形成,从而可间接地反映ＩＬ１ 参与了ＣＣｌ４ 导致肝损伤的发病过程。     

Ethnicity, alcohol drinking and changes in transaminase activity among heavy drinkers

BACKGROUND: Liver cirrhosis mortality differs by ethnicity in the United States. Some studies suggest alcohol sensitivity may contribute to this finding. This analysis evaluated if alcohol-associated changes in aspartate aminotransferase (AST) and alanine transaminase (ALT) differed by ethnicity among heavy drinkers. METHODS: Subjects included 1691 subjects from Project MATCH, a multicenter alcohol use disorders treatment trial. Changes in AST and ALT over 15 months were modeled as functions of ethnicity, age, gender, time, study site and alcohol use. The main focus was on ethnic differences in changes in transaminase activity occurring with changes in alcohol use. RESULTS: At all levels of alcohol consumption AST was lower in non-Hispanic whites relative to African Americans and Mexican Americans. Changes in AST associated with changes in alcohol use did not vary by ethnicity. ALT significantly differed only between Mexican Americans and non-Hispanic whites. Similar to AST, alcohol-associated ALT change did not differ by ethnicity. CONCLUSIONS: Among individuals with alcohol use disorders participating in a treatment trial, the effect of alcohol drinking on transaminase activity did not vary by ethnicity. However, in the general population, alcohol may still interact with other factors in mediating ethnic differences in cirrhosis mortality.     

The effect of serotonin reuptake inhibitors on hepatic injury induced by carbon tetrachloride

The aim of the present study was to investigate the effect of several drugs acting on serotonergic neurotransmission on the development of hepatocellular injury caused by carbon tetrachloride (CCl₄) in rats. Liver damage was induced in rats by administration of CCl₄ (2.8 ml/kg in olive oil, orally). Sertraline, citalopram, or fluvoxamine were administered orally once daily in association with CCl₄ and for 1 week thereafter. Sibutramine was administered 1 week prior to the toxic agent and for 3 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. In CCl₄-treated rats, sertraline (10, 20 mg/kg) reduced serum alanine aminotransferase (ALT) levels by 41.8% and 53.4%, respectively, compared to controls. Serum aspartate aminotransferase (AST) levels decreased by 37.4% and 58.2%, respectively, while alkaline phosphatase (ALP) decreased by 40.5% and 59.3%, respectively. Treatment with citalopram (5, 10, 20 mg/kg) reduced serum ALT levels by 29.8%, 35.6%, and 43.8%, AST levels by 24.2%, 29.9%, and 43%, and ALP by 17.8%, 35%, and 48.9%, respectively. Fluvoxamine (5, 10, 20 mg/kg) dose-dependently reduced the elevation of ALT levels by 42.6%, 49.9%, and 51.9%, AST levels by 40.2%, 44.6%, and 61.6%, and ALP by 8.3%, 46.8%, and 52.7%, respectively. Given as a pretreatment, sibutramine (5, 10, 20 mg/kg) reduced serum ALT levels by 52.1%, 52.2%, and 57.5%, AST levels by 53.6%, 58.4%, and 59.4%, and ALP by 46.8%, 67.6%, and 72.2%, respectively. Histopathological and histochemical examinations also indicated that CCl₄-induced liver injury was less severe after treatment with the test drugs than in the CCl₄ control groups. It is concluded that the administration of drugs with serotonin reuptake inhibitory properties is associated with a reduction in experimental liver injury induced by CCl₄.     

The dopamine agonist piribedil exerts hepatoprotective effects on carbon tetrachloride-induced hepatic damage

This study aimed to investigate the effect of piribedil, a drug used for the treatment of Parkinson’s disease and which has direct dopaminergic stimulating action, on the acute hepatic injury in mice. Hepatotoxicity was induced by CCl₄ orally (0.28 ml/kg). Piribedil at three dose levels (4.5, 9, or 18 mg/kg) or silymarin (25 mg/kg) was given orally daily for 7 days, starting at time of administration of CCl₄. Liver damage was assessed by determining liver serum enzyme activities and by hepatic histopathology. Piribedil administration lessened the increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) and also prevented the development of hepatic necrosis caused by CCl₄. The effect of piribedil was dose-dependent one. Piribedil administered at the above doses caused significant reduction in the elevated plasma ALT by ?36.3%, ?42.8%, and ?52.4% and ALP by ?25%, ?36.9%, and ?57.1%, respectively. AST decreased by ?36.4% and ?46.2% by piribedil at 9 or 18 mg/kg, respectively. In comparison, the elevated serum ALT, AST, and ALP levels decreased to ?69.6%, ?64.2%, and ?68.5% of control values, respectively, by silymarin. Histopathologic examination of the livers of CCl₄-treated mice administered piribedil at 9 mg/kg showed noticeable amelioration of the liver tissue damage, while piribedil at 18 mg/kg resulted in restoration of the normal architecture of the liver tissue as well as noticeable increase in the protein content of hepatocytes. It is concluded that administration of the dopaminergic agonist piribedil in a model of liver injury induced by CCl₄ results in amelioration of liver damage.