Vanillin attenuates thioacetamide-induced renal assault by direct and indirect mediation of the TGFß, ERK and Smad signalling pathways in rats.

Inflammation and fibrosis are two pathological features of chronic kidney disease (CKD). Renal fibrosis is considered to be one of the most important conditions, as it may be the result of excessive extracellular matrix protein production and deposition, or prolonged exposure to nephrotoxic substances or drugs. Unfortunately, no suitable therapies or medications are currently available to prevent renal fibrosis. We conducted this study for the evaluation of the protective potential of vanillin by reversing TAA (250 mg/kg TAA for 6 weeks) induced renal injury in rats. The concentrations of the proteins tumour necrosis factor alpha (TNFα), interleukin-6 (IL-6), extracellular signal regulated kinase 1/2 (Erk1/2), and transforming growth factor beta-1 (TGF-ß1) in kidney tissues were assessed using ELISA. Kidney Injury Molecule-1 (KIM-1) and mothers against decapentaplegic homologue 2, 3 (SMAD 2, 3) expressions were evaluated using real time PCR. We also estimated the expression of α-smooth muscle actin (α-SMA) using immunohistochemistry. Treatment with vanillin (100 mg/kg) significantly ameliorated kidney Injury and improved the kidney function. Vanillin treatment also significantly decreased the malondialdehyde (MDA) content, and elevated glutathione peroxidase (GPx) and catalase (CAT) activities in kidney tissues. Vanillin also reduced α-SMA renal expression and TNFα, IL-6, TGF-ß1, and Erk1/2 renal levels. Vanillin significantly decreased the expression of the genes encoding KIM-1 and SMAD 2, 3 and ameliorated histological abnormalities in kidney architecture. Our molecular docking findings showed that vanillin has a good binding mode inside TGF-ß type I receptors (ALK5) biding site.

Dasatinib ameliorates thioacetamide-induced liver fibrosis: modulation of miR-378 and miR-17 and their linked Wnt/ß-catenin and TGF-ß/smads pathways.

Hepatic stellate cells activation (HSCs) plays a crucial role in the pathogenesis of liver fibrosis. Specific microRNAs have been suggested to affect the activation of HSCs via various signalling pathways including TGF-ß/smads and Wnt/ß-catenin pathways. Dasatinib is a multitarget inhibitor of many tyrosine kinases has recently studied for its anti-fibrotic effects in a variety of fibrous diseases. This study investigated the role of modulation of miRNA-378 and miRNA-17 in the pathogenesis of liver fibrosis through altering Wnt/ß-catenin and TGF-ß/smads pathways and evaluated the beneficial effect of the tyrosine kinase inhibitor, dasatinib, in thioacetamide-induced liver fibrosis model in mice. Treatment with dasatinib down-regulated miRNA-17 expression, leading to the restoration of WiF-1 and smad-7 which cause the inhibition of both Wnt/ß-catenin and TGF-ß/smads signalling. In addition, it upregulated miRNA-378 leading to the decrease of Wnt-10 which contributes to the suppression of activated HSCs.

Brassica juncea L. (Mustard) Extract Silver NanoParticles and Knocking off Oxidative Stress, ProInflammatory Cytokine and Reverse DNA Genotoxicity.

Detoxification is one of the main vital tasks performed by the liver. The purpose of this study was to investigate whether mustard in its normal or nanoparticles could confer a protective/therapeutic effect against TAA-induced acute liver failure in experimental animal models. Mustard ethanolic extract was analyzed by HPLC/MS. To induce liver failure, male rats were injected with 350 mg/kg bw TAA IP, then treated orally with a dose of 100 mg/kg for 15 d of mustard extract and its nanoform before and following induction. The levels of serum liver functions, total cholesterol (TCHo), total glyceride (TG), total bilirubin (TBIL), hepatic malonaldhyde (MDA) and nitric oxide (NO),glutathione (GSH), sodium oxide dismutase (SOD), as well as tumor necrosis factor (TNF-α,) and interleukin 6 (IL-6), were estimated. DNA genotoxicity and hepatic pathology, and immunohistologic (IHC) changes were assayed. The antioxidant content of Phenolic acids, flavonoids in mustard ethanolic extract substantially decreased the levels of ALT, AST, ALP and rehabilitated the histopathological alterations. In addition, nanoforms of mustard ethanol extract have notably increased the levels of GSH, SOD and significantly reduced the levels of MDA. The expression levels of TNF-α and IL-6 in serum and tissue were markedly downregulated. DNA genotoxicity was significantly reversed. Mustard introduced a protective and medicinal effect against TAA in both its forms.

Protective effect of dioscin against thioacetamide-induced acute liver injury via FXR/AMPK signaling pathway in vivo.

Our previous works showed that dioscin, a natural product, could protect liver from acute liver damages induced by dimethylnitrosamine, ethanol, carbon tetrachloride and acetaminophen. However, the effect of dioscin on thioacetamide (TAA)-induced acute liver injury still remained unknown. The purpose of this study was to investigate whether dioscin confers a protective effect against TAA-induced acute liver injury in rats and mice. The results showed that dioscin decreased the serum levels of ALT, AST, and rehabilitated histopathological changes compared with the model groups. In addition, dioscin obviously increased the levels of GSH, GSH-Px, SOD, and significantly reduced MDA levels compared with the model groups. Mechanistic study showed that dioscin significantly up-regulated the expression levels of FXR, p-AMPKα, and then increased the expression levels of Nrf2, HO-1, NQO-1, GCLM and GST. Furthermore, dioscin obviously down-regulated the expression levels of NF-κB (p65), ICAM-1, HMGB1, COX-2, TNF-α, IL-1ß and IL-6. Taken together, dioscin showed protective effect against TAA-induced acute liver injuries in rats and mice and the effects might be obtained through inhibiting oxidative stress and inflammation via FXR/AMPK signal pathway. These findings provided a new insight on the role of doscin in the treatment of acute liver injury.

Effect of coriander on thioacetamide-induced hepatotoxicity in rats.

Thioacetamide (TAA) is a potent hepatotoxin that causes centrilobulal necrosis and nephrotoxic damage following acute administration. Prolonged exposure to TAA can result in bile duct proliferation and liver cirrhosis histologically similar to that caused due to viral hepatitis infection. Coriander in food increases the antioxidant content, acting as a natural antioxidant and inhibiting undesirable oxidation processes. The present study investigated the antioxidant activity of Coriandrum sativum on TAA-induced hepatotoxicity in the male rats. Phenolic content and antioxidant activity were evaluated in the coriander leaves and seeds. Forty-eight adult male rats were divided into four groups. Group I (control), group II (TAA injected rats), group III (TAA injected rats fed coriander leaves) and group IV (TAA injected rats fed coriander seeds). The results revealed that serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities were significantly increased in the groups II, III and IV as compared to the normal control. Oxidative stress in the group II was manifested by a significant rise in nitric oxide (NO), thiobarbituric acid reactive substance (TBARS) levels and myloperoxidase (MPO) activities in the liver tissues as compared with the control group. Rats fed with coriander leaves and seeds showed a decrease in the serum ALT, AST and ALP activities and in the liver NO and TBARS levels as compared to the group II. Histopathological study revealed that coriander feeding attenuated TAA-induced hepatotoxicity in the rats. In conclusion, coriander leaves attenuate hepatotoxicity induced by TAA more than that of seeds due to the higher content of phenolic compounds and antioxidants in the leaves of coriander. Liver of rats intoxicated with TAA exhibited advanced CIRRHOSIS: in the form of macronodular and micronodular structure surrounded by fibrous tissue. Treatment with coriander leaves and seeds helps in improving the adverse effect of TAA-induced hepatotoxicity; also the histological study confirms this finding.

Inhibitory effect of α-lipoic acid on thioacetamide-induced tumor promotion through suppression of inflammatory cell responses in a two-stage hepatocarcinogenesis model in rats.

To investigate the protective effect of α-lipoic acid (a-LA) on the hepatocarcinogenic process promoted by thioacetamide (TAA), we used a two-stage liver carcinogenesis model in N-diethylnitrosamine (DEN)-initiated and TAA-promoted rats. We examined the modifying effect of co-administered a-LA on the liver tissue environment surrounding preneoplastic hepatocellular lesions, with particular focus on hepatic macrophages and the mechanism behind the decrease in apoptosis of cells surrounding preneoplastic hepatocellular lesions during the early stages of hepatocellular tumor promotion. TAA increased the number and area of glutathione S-transferase placental form (GST-P)(+) liver cell foci and the numbers of proliferating and apoptotic cells in the liver. Co-administration with a-LA suppressed these effects. TAA also increased the numbers of ED2(+), cyclooxygenase-2(+), and heme oxygenase-1(+) hepatic macrophages as well as the number of CD3(+) lymphocytes. These effects were also suppressed by a-LA. Transcript levels of some inflammation-related genes were upregulated by TAA and downregulated by a-LA in real-time RT-PCR analysis. Outside the GST-P(+) foci, a-LA reduced the numbers of apoptotic cells, active caspase-8(+) cells and death receptor (DR)-5(+) cells. These results suggest that hepatic macrophages producing proinflammatory factors may be activated in TAA-induced tumor promotion. a-LA may suppress tumor-promoting activity by suppressing the activation of these macrophages and the subsequent inflammatory responses. Furthermore, a-LA may suppress tumor-promoting activity by suppressing the DR5-mediated extrinsic pathway of apoptosis and the subsequent regeneration of liver cells outside GST-P(+) foci.

Bioactive compounds, antioxidant potential, and hepatoprotective activity of sea cucumber (Holothuria atra) against thioacetamide intoxication in rats.

OBJECTIVE: The identification of the active phenolic compounds in the mixed extract of sea cucumber (Holothuria atra) body wall by high-performance liquid chromatography and an assessment of its hepatoprotective activity against thioacetamide-induced liver fibrosis in rats. METHODS: Female Swiss albino rats were divided into four groups: normal controls; oral administration of a sea cucumber mixed extract (14.4 mg/kg of body weight) on days 2, 4, and 6 weekly for 8 consecutive weeks; intoxication with thioacetamide (200 mg/kg of body weight, intraperitoneally) on days 2 and 6 weekly for 8 wk; and oral administration of a sea cucumber extract and then intoxication with thioacetamide 2 h later for 8 wk. RESULTS: High-performance liquid chromatographic analysis of the sea cucumber mixed extract revealed the presence of some phenolic components, such as chlorogenic acid, pyrogallol, rutin, coumaric acid, catechin, and ascorbic acid. In vitro studies have shown that the extract has a high scavenging activity for the nitric oxide radical, a moderate iron-chelating activity, and a weak inhibitory effect of lipid peroxidation. The subchronic oral administration of sea cucumber extract to the rats did not show any toxic side effects but increased hepatic superoxide dismutase and glutathione peroxidase activities. The coadministration of sea cucumber extract and thioacetamide (protection modality) normalized serum direct bilirubin, alanine and aspartate aminotransferases, hepatic malondialdehyde, and hydroxyproline concentrations and antioxidant enzyme activities. In addition, the histologic examination of liver sections from the protection group that were stained with hematoxylin and eosin showed substantial attenuation of the degenerative cellular changes and regressions in liver fibrosis and necrosis induced by the thioacetamide intoxication. CONCLUSION: Sea cucumber mixed extract contains physiologically active phenolic compounds with antioxidant activity, which afforded a potential hepatoprotective activity against thioacetamide-induced liver injury in a rat model.

Coffee and caffeine protect against liver injury induced by thioacetamide in male Wistar rats.

Coffee intake has been inversely related to the incidence of liver diseases, although there are controversies on whether these beneficial effects on human health are because of caffeine or other specific components in this popular beverage. Thus, this study evaluated the protective effects of coffee or caffeine intake on liver injury induced by repeated thioacetamide (TAA) administration in male Wistar rats. Rats were randomized into five groups: one untreated group (G1) and four groups (G2-G5) treated with the hepatotoxicant TAA (200 mg/kg b.w., i.p.) twice a week for 8 weeks. Concomitantly, rats received tap water (G1 and G2), conventional coffee (G3), decaffeinated coffee (G4) or 0.1% caffeine (G5). After 8 weeks of treatment, rats were killed and blood and liver samples were collected. Conventional and decaffeinated coffee and caffeine intake significantly reduced serum levels of alanine aminotransferase (ALT) (p < 0.001) and oxidized glutathione (p < 0.05), fibrosis/inflammation scores (p < 0.001), collagen volume fraction (p < 0.01) and transforming growth factor ß-1 (TGF-ß1) protein expression (p ≤ 0.001) in the liver from TAA-treated groups. In addition, conventional coffee and caffeine intake significantly reduced proliferating cellular nuclear antigen (PCNA) S-phase indexes (p < 0.001), but only conventional coffee reduced cleaved caspase-3 indexes (p < 0.001), active metalloproteinase 2 (p ≤ 0.004) and the number of glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions (p < 0.05) in the liver from TAA-treated groups. In conclusion, conventional coffee and 0.1% caffeine intake presented better beneficial effects than decaffeinated coffee against liver injury induced by TAA in male Wistar rats.

Polaprezinc prevents ongoing thioacetamide-induced liver fibrosis in rats.

AIMS: Cirrhotic patients commonly have a liver zinc deficiency, which may aggravate liver fibrosis due to the lack of antioxidative effects of zinc. This study examined the ability of polaprezinc, N-(3-aminopropionyl)-l-histidinato zinc, to prevent fibrosis in a rat model of thioacetamide (TAA)-induced hepatic fibrosis. MAIN METHODS: Liver cirrhosis was induced by orally administering TAA for 20 weeks. The rats were cotreated with one of the following for the last 10 weeks of TAA treatment: (1) polaprezinc (50 or 200mg/kg/day); (2) l-carnosine (155 mg/kg/day), which contained equal amounts of l-carnosine as 200mg/kg/day polaprezinc; (3) zinc sulfate (112 mg/kg/day) or (4) zinc-l-aspartic complex (317.8 mg/kg/day). Both zinc supplementations contained equal amounts of zinc as high-dose polaprezinc. KEY FINDINGS: Hepatic zinc levels fell significantly in rats treated with TAA for 20 weeks. Cotreating with high-dose polaprezinc and zinc-l-aspartic complex for 10 weeks prevented hepatic zinc loss. Hepatic hydroxyproline and tissue inhibitor of metalloproteinases-1 (TIMP-1) were significantly higher in rats treated with TAA for 20 weeks than 10 weeks, whereas polaprezinc prevented changes in these fibrosis markers and reduced hepatic transforming growth factor-ß1 protein concentration, macroscopic and histologic changes. TAA caused oxidative stress-related changes in the liver that were prevented by high-dose polaprezinc and partially by zinc-l-aspartic complex. Treatment with l-carnosine, low-dose polaprezinc or zinc sulfate for 10 weeks did not affect liver fibrosis progression or oxidative stress-related changes. SIGNIFICANCE: Polaprezinc may prevent ongoing fibrosis by preventing zinc depletion, oxidative stress and fibrosis markers in cirrhotic livers.

Tamarix gallica ameliorates thioacetamide-induced hepatic oxidative stress and hyperproliferative response in Wistar rats.

Tamarix gallica, a hepatic stimulant and tonic, was examined for its ability to inhibit thioacetamide (TAA)-induced hepatic oxidative stress, toxicity and early tumor promotion response in male Wistar rats. TAA (6.6 mmol/kg body wt. i.p) enhanced lipid peroxidation, hydrogen peroxide content, glutathione S-transferase and xanthine oxidase with reduction in the activities of hepatic antioxidant enzymes viz., glutathione peroxidase, superoxide dismutase and caused depletion in the level of hepatic glutathione content. A marked increase in liver damage markers was also observed. TAA treatment also enhanced tumor promotion markers, ornithine decarboxylase (ODC) activity and [3H] thymidine incorporation into hepatic DNA. Pretreatment of rats orally with Tamarix gallica extract (25 and 50 mg/kg body weight) prevented TAA-promoted oxidative stress and toxicity. Prophylaxis with Tamarix gallica significantly reduced the susceptibility of the hepatic microsomal membrane for iron-ascorbate induced lipid peroxidation, H2O2 content, glutathione S-transferase and xanthine oxidase activities. There was also reversal of the elevated levels of liver marker parameters and tumor promotion markers. Our data suggests that Tamarix gallica is a potent chemopreventive agent and may suppress TAA-mediated hepatic oxidative stress, toxicity, and tumor promotion response in rats.

Depletion of Kupffer cell function by gadolinium chloride attenuates thioacetamide-induced hepatotoxicity. Expression of metallothionein and HSP70.

Kupffer cell function plays an important role in drug-induced liver injury. Thus, gadolinium chloride (GD), by selectively inactivating Kupffer cells, can alleviate drug-induced hepatotoxicity. The effect of GD was studied in reference to metallothionein and heat shock proteins expression in an in vivo model of liver necrosis induced by thioacetamide. Rats, pre-treated or not with GD (0.1 mmol/kg), were intraperitoneally injected with thioacetamide (6.6 mmol/kg), and samples of blood and liver were obtained at 0, 12, 24, 48, 72 and 96 hr. Parameters related to liver damage, Kupffer cell function, microsomal FAD monooxygenase activity, oxidative stress, and the expression of metallothionein and HSP70 were determined. GD significantly reduced serum myeloperoxidase activity and serum concentration of TNF alpha and IL-6, increased by thioacetamide. The extent of necrosis, the degree of oxidative stress and lipoperoxidation and microsomal FAD monooxygenase activity were significantly diminished by GD. The effect of GD induced noticeable changes in the expression of both metallothionein and HSP70, compared to those induced by thioacetamide. We conclude that GD pre-treatment reduces thioacetamide-induced liver injury and enhances the expression of metallothionein and HSP70. This effect, parallel to reduced levels of serum cytokines and myeloperoxidase activity, demonstrates that Kupffer cells are involved in thioacetamide-induced liver injury, the degree of contribution being approximately 50%.

Zinc supplementation attenuates thioacetamide-induced liver injury and hyperglycemia in mice.

Zinc supplementation has been shown to improve not only liver dysfunction but also glucose intolerance in subjects with liver cirrhosis. In this study, we investigated the effects of zinc supplementation on the changes in circulating levels of tumor necrosis factor-alpha and total antioxidant capacity in mice with thioacetamide-induced liver injury. The protective effect of concurrent zinc administration for thioacetamide-induced hepatotoxicity was also examined. The results showed that zinc treatment significantly attenuated thioacetamide-induced liver injury and hyperglycemia. Furthermore, thioacetamide-induced hepatotoxicity was markedly weakened by the simultaneous zinc administration. These effects might be attributed to reduced tumor necrosis factor-alpha production and elevated total antioxidant capacity induced by the mineral. Our data suggest that zinc supplementation might be beneficial for the subjects with a high susceptibility to liver injury.

Dietary nucleotide supplementation reduces thioacetamide-induced liver fibrosis in rats.

Dietary nucleotides reportedly promote functionality and repair in fibrotic liver. Liver fibrosis is characterized by an excessive accumulation of extracellular matrix components, which lead to the impairment of the hepatic function. The aim of this work was to evaluate the influence of dietary nucleotides on liver fibrosis induced by thioacetamide and to elucidate the mechanism by which nucleotides exert their protective effects. Rats consumed ad libitum 300 mg/L thioacetamide in drinking water and were pair-fed diets with (group TN) or without nucleotides (group TS) for 4 mo. Liver histology and extracellular matrix components, liver collagenase and prolyl 4-hydroxylase activities, and tissue inhibitor of metalloproteinases-1 were assessed. The degree of fibrosis was lower in group TN than in group TS. Group TN had lower hepatic concentration of hydroxyproline (P < 0.05), collagen type I (P = 0.12) and type III (P = 0.20), fibronectin (P = 0.05), laminin (P = 0.11) and desmin (P = 0.07), higher collagenolytic activity (P < 0.05), lower prolyl 4-hydroxylase activity (P < 0.05) and lower prolyl 4-hydroxylase (P = 0.10) and tissue inhibitor of metalloproteinase-1 (P = 0.06) expression than group TS. Moreover, expression of tissue inhibitor of the metalloproteinases-1 gene was lower in group TN than in group TS (P < 0.05). These data indicate that the reduction of liver fibrosis in nucleotide-supplemented rats may rely on the enhancement of collagenase activity and the reduction of collagen content and maturation.

Evaluation of hepatoprotective potential of jigrine post-treatment against thioacetamide induced hepatic damage.

Jigrine a polypharmaceutical herbal formulation containing aqueous extracts of 14 medicinal plants developed on the principles of unani system of medicine is used for liver ailments. The hepatoprotective potential of jigrine post-treatment at the dose of 0.5 ml/kg per day p.o. for 21 days was evaluated against thiocetamide induced liver damage in rats. Biochemical parameters like AST, ALT in serum and TBARS and glutathione in tissues were estimated to assess liver function. Data on the biochemical parameters revealed hepatoprotective potential of jigrine post-treatment against thioacetamide induced hepatotoxicity in rats. Silymarin used as reference standard also exhibited significant hepatoprotective activity on post-treatment against thioacetamide-induced hepatotoxity in rats. The biochemical observations were supplemented with histopathological examination of rat liver sections.

The protective effect of taurine against thioacetamide hepatotoxicity of rats.

Thioacetamide (TAA) administration (three consecutive intraperitoneal injections of 400 mg/kg at 24-h interval) to rats resulted in hepatic injury as assessed by the measurement of serum transaminase activities and histopathological findings. This treatment caused an increase in the levels of malondialdehyde (MDA), diene conjugates (DCs) and glutathione (GSH) and the activity of superoxide dismutase SOD ), and a decrease in the levels of vitamins E and C and the activity of glutathione peroxidase (GSH-Px) in the liver of rats. Taurine administration (400 mg/kg, i.p., every 12 h and started 24 h prior to the first TAA injection) was found to decrease serum transaminase activities and hepatic lipid peroxidation without any significant change in hepatic antioxidant system. Histopathological findings also suggested that taurine has ameliorated effect on TAA-induced hepatic necrosis. These results indicate that taurine treatment, together with TAA administration, diminished the severity of the liver injury by decreasing oxidative stress due to its possible scavenger effect.

Xanthine oxidase-derived reactive oxygen metabolites contribute to liver necrosis: protection by 4-hydroxypyrazolo[3,4-d]pyrimidine.

Xanthine oxidase (XO) generates reactive oxygen metabolites (ROM) as a by-product while catalyzing their reaction. The present study implicates these ROM in the pathogenesis of liver necrosis produced in rats by the intraperitoneal administration of thioacetamide (TAA; 400 mg/kg b.wt.). After 16 h of TAA administration, the activity of rat liver XO increased significantly compared to that of the control group. At the same time, the level of serum marker enzymes of liver necrosis (aminotransferases and alkaline phosphatase) and tissue malondialdehyde content also increased in TAA treated rats. Tissue malondialdehyde concentration is an indicator of lipid peroxidation and acts as a useful marker of oxidative damage. Pretreatment of rats with XO inhibitor (4-hydroxypyrazolo[3,4-d]pyrimidine; allopurinol (AP)) followed by TAA could lower the hepatotoxin-mediated rise in malondialdehyde level as well as the level of marker enzymes associated with liver necrosis. The survival rate also increased in rats given AP followed by the lethal dose of TAA. In either case, the effect of AP was dose-dependent. Results presented in the paper indicate that increased production of XO-derived ROM contributes to liver necrosis, which can be protected by AP.

Curative effect of picroliv on primary cultured rat hepatocytes against different hepatotoxins: an in vitro study.

Picroliv, the standardized active principle from the plant Picrorhiza kurrooa showed significant curative activity in vitro in primary cultured rat hepatocytes against toxicity induced by thioacetamide (200 microg/mL), galactosamine (400 microg/mL), and carbon tetrachloride (3 microl/mL). Activity was assessed by determining the change in hepatocyte viability and rate of oxygen uptake and other biochemical parameters (GOT, GPT, and AP). The toxic agents alone produced a 40-62% inhibition of cell viability and a reduction of biochemical parameters after 24 h of incubation at 37 degrees C which (on removal of the toxic agents) was reversed after further incubation for 48 h. Incubation of damaged hepatocytes with picroliv exhibited a concentration- (1-100 microg/mL) dependent curative effect in restoring altered viability parameters. The results warrant the use of this in vitro system as an alternative for in vivo assessment of hepatoprotective activity of new agents.

Inhibition of halothane-induced lipid peroxidation by misoprostol without hepatoprotection.

In mice, the synthetic prostaglandin derivative misoprostol failed to protect against liver damage induced by acetaminophen, carbon terachloride,1,1-dichloroethylene or thioacetamide. In rats, misoprostol (20-100 micrograms/kg p.o.) markedly reduced early increments of plasma enzyme activities (glutamate-pyruvate-transaminase, GPT; sorbitol dehydrogenase, SDH) in a model of halothane-induced liver injury; the most effective dose in this respect (20 micrograms/kg) significantly depressed halothane-induced ethane exhalation indicating in vivo lipid peroxidation. Repeated treatment with misoprostol (20 micrograms/kg p.o.) still diminished halothane-induced elevations of enzyme activities over 48 h, but failed to prove hepatoprotection by histomorphological examinations. It is concluded that the antiperoxidative properties of misoprostol are not paralleled by an hepatoprotection, which was indicated by significant reductions of liver-specific plasma enzyme activities, but not confirmed by the morphological picture.

Effects of calcium channel blocking agents on calcium and centrilobular necrosis in the liver of rats treated with hepatotoxic agents.

Carbon tetrachloride, chloroform, dimethylnitrosamine, thioacetamide or acetaminophen was each administered to rats in a single hepatotoxic dose. Nifedipine, verapamil or chlorpromazine was administered in association with the hepatotoxic agents to determine if calcium channel blocking agents would prevent an increase in liver cell calcium associated with hepatotoxicity and to determine if these agents would protect against the development of centrilobular necrosis. Following a latent period different for each toxic agent, a 4- to 18-fold increase in liver cell calcium content had occurred by 24 hr. The calcium increase and the centrilobular necrosis (mean histologic score) were correlated. A relatively high calcium to necrosis ratio was obtained with dimethylnitrosamine, thioacetamide and acetaminophen. A lesser calcium to necrosis ratio was obtained with chloroform and carbon tetrachloride, the two toxic agents that destroyed the intracellular calcium sequestration activity of the liver endoplasmic reticulum. Nifedipine or chlorpromazine, administered prior to and 7 hr after the toxic agent, completely prevented the centrilobular necrosis caused by thioacetamide, carbon tetrachloride and acetaminophen; almost completely prevented necrosis with dimethylnitrosamine; and provided partial protection against chloroform toxicity. Two doses of verapamil provided partial protection against necrosis when carbon tetrachloride was the toxic agent and provided almost complete protection with dimethylnitrosamine. A reduction in liver cell calcium was associated with the protective action of the three calcium channel blocking agents. These findings are compared with earlier studies of the protective effects of calcium channel blocking agents in cardiac ischemia.

Prevention of thioacetamide-induced liver necrosis by prior aminoacetonitrile or imidazole administration.

Prior administration of aminoacetonitrile (AAN) or imidazole but not isoxazole to rats, was able partially to prevent thioacetamide (TAC)-induced liver necrosis at 24 h. AAN and isoxazole did not prolong the pentobarbital sleeping time of the rats, while imidazole did. These and previous observations suggest a possible participation of non-cytochrome P-450 (P-450)-dependent aminoxidases in TAC activation to a necrogenic metabolite.