• YAKHAK HOEJI
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• v.40 no.6
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• pp.727-733
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• 1996

2-(Allylthio)pyrazine is effective in selectively suppressing constitutive and inducible expression of cytochrome P450 2E1. The effect of 2-(allylthio)pyrazine against potentiat ed chemical injury was studied in rats. Vitamin-A pretreatment of rats substantially increased carbon tetrachloride hepatotoxicity, as supported by an ~4-fold increase in serum alanine aminotransferase (ALT) activity. Concomitant pretreatment of rats with 2-(allylthio)pyrazine at the daily dose of 200mg/kg resulted in a 76% decrease in vitamin-A-potentiated hepatotoxicity, which supported the possibility that 2-(allylthio)pyrazine protects the liver against chemical-induced hepatic injury by the mechanism associated with Kupffer cell inactivation. Pyridine pretreatment caused substantial enhancement in carbon tetrachloride hepatotoxicity. 2-(Allylthio)pyrazine treatment of rats reduced the pyridine-potentiated toxicity in a dose-dependent manner. Animals treated with both pyridine and 2-(allylthio)pyrazine prior to intoxicating dose of CCl$_4$ resulted in 85% and 47% decreases in pyridine-increased triglycerides and cholesterol levels in the liver. The protective effect of 2-(allylthio)pyrazine on the DNA strand breakage induced by benzenetriol was assessed by measuring the conversion of supercoiled ${\Phi}x$-174 DNA to the open relaxed form. 2-(Allylthio)pyrazine blocked the benzenetriol-induced conversion of supercoiled DNA to open circular form in a dose-dependent manner. The presence of 2-(allylthio)pyrazine at the doses from I to 10mM in the incubation mixture containing 5 ${\mu}$M benzenetriol completely protected benzenetriol-induced DNA strand breakage with the EC50 for the 2-(allylthio)pyrazine blocking being noted as ~220 ${\mu}$M, whereas allyl disulfide exerted protecting effect at relatively high concentrations (i.e. ~850 ${\mu}$M), suggesting that 2-(allylthio)pyrazine effectively scavenges the reactive oxygen species. These results provide evidence that 2-(allylthio)pyrazine blocks vitamin A- or pyridine-potentiated CCl$_4$ hepatotoxicity and that the agent is active in protecting DNA by scavenging the reactive oxygen species.

• Nutrition Research and Practice
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• v.4 no.2
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• pp.93-98
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• 2010

Our previous study demonstrated that methanolic extract of Chrysanthemum zawadskii Herbich var. latilobum Kitamura (Compositae) has the potential to induce detoxifying enzymes such as NAD(P)H:(quinone acceptor) oxidoreductase 1 (EC 1.6.99.2) (NQO1, QR) and glutathione S-transferase (GST). In this study we further fractionated methanolic extract of Chrysanthemum zawadskii and investigated the detoxifying enzyme-inducing potential of each fraction. The fraction (CZ-6) shown the highest QR-inducing activity was found to contain (+)-(3S,4S,5R,8S)-(E)-8-acetoxy-4-hydroxy-3-isovaleroyloxy-2-(hexa-2,4-diynyliden)-1,6-dioxaspiro [4,5] decane and increased QR enzyme activity in a dose-dependent manner. Furthermore, CZ-6 fraction caused a dose-dependent enhancement of luciferase activity in HepG2-C8 cells generated by stably transfecting antioxidant response element-luciferase gene construct, suggesting that it induces antioxidant/detoxifying enzymes through antioxidant response element (ARE)-mediated transcriptional activation of the relevant genes. Although CZ-6 fraction failed to induce hepatic QR in mice over the control, it restored QR activity suppressed by $CCl_4$ treatment to the control level. Hepatic injury induced by $CCl_4$ was also slightly protected by pretreatment with CZ-6. In conclusion, although CZ-6 fractionated from methanolic extract of Chrysanthemum zawadskii did not cause a significant QR induction in mice organs such as liver, kidney, and stomach, it showed protective effect from liver damage caused by $CCl_4$.

• Journal of Veterinary Clinics
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• v.24 no.3
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• pp.384-391
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• 2007

This study was conducted to clarify the effects of the Korean raisin (Hovenia dulcis Thunb) extracts and polyherbal extracts consisted of 6 types herbal extracts including HDT (HDTmix) on $CCl_4$ induced organ damages. Extracts were prepared by autoclave ($121^{\circ}C$, 15 psi, 3 hours) and filtered with nylon cloth and filter paper then freezing dried. Male Sprague-Dawley rats $(200^{\circ}{\ae}20g)$ were used as experimental groups, which were divided into 5 groups; intact control group (100 mg/kg), $CCl_4$ dosing group (100 mg/kg), $CCl_4$ dosing after HDT extract dosing group (100 mg/kg), $CCl_4$ dosing after HDTmix dosing group (100 mg/kg), Silymarin dosing group (5 mg/kg) after all test articles were orally dosed once a day for 28 days. They were sacrifiled under ether anesthesia. HDT extracts and HDTmix dramatically inhibits the $CCl_4$ intoxicated hepato/nephropathies with immuno-suppress changes on the spleen. They showed more dramatical protective effects on most of specific organs compared to that of Silymarin 5 mg/kg except for hepatoprotective effects in which, quite similar effects were detected. In addition, HDT extracts showed synergic effects with other types of herbal extracts because HDTmix showed more favorable protective effects on the all specific organs showing $CCl_4-related$ histopathological changes compared to HDT extracts.

• The Korean Journal of Pharmacology
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• v.32 no.3
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• pp.407-416
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• 1996

The reactive intermediates formed during the metabolism of therapeutic agents, toxicants and carcinogens by cytochromes P450 are frequently capable of covalently binding to tissue macromolecules and causing tissue damage. It has been shown that YH439, a congener of malotilate, is effective in suppressing hepatic P450 2E1 expression. The present study was designed to further establish the mechanistic basis of YH439 protection against toxicant by assessing its effects against chemical-mediated potentiated hepatotoxicity. Retinoyl palmitate (Vit-A) pretreatment of rats for 7 days substantially enhanced carbon tetrachloride hepatotoxicity, as supported by an ${\sim}5-fold$ increase in serum alanine aminotransferase (ALT) activity, as compared to $CCl_4$ treatment alone. The elevation of ALT activity due to Vit-A was completely blocked by the treatment of $GdCl_3$ a selective inhibitor of Kupffer cell activity. Concomitant pretreatment of rats with both YH439 and Vit-A resulted in a 94% decrease in Vit-A-potentiated $CCl_4$ hepatotoxicity. YH439 was also effective against propyl sulfide-potentiated $CCl_4-induced$ hepatotoxicity. Whereas propyl sulfide (50 mg/kg, 7d) enhanced $CCl_4-induced$ hepatotoxicity by >5-fold, relative to $CCl_4$ treatment alone, concomitant treatment of animals with both propyl sulfide and YH439 at the doses of 100 and 200 mg/kg prevented propyl sulfide-potentiated $CCl_4$ hepatotoxicity by 35% and 90%, respectively. Allyl sulfide, a suppressant of hepatic P450 2E1 expression, completely blocked the propyl sulfide-enhanced hepatotoxicity, indicating that propyl sulfide potentiation of $CCl_4$ hepatotoxicity was highly associated with the expression of P450 2E1 and that YH439 blocked the propyl sulfide-enhanced hepatotoxicity through modulation of P450 2E1 levels. Propyl sulfide- and $CCl_4-induced$ stimulation of lipid peroxidation was also suppressed by YH439 in a dose-related manner, as supported by decreases in malonedialdehyde production. The role of P450 2E1 induction in the potentiation of $CCl_4$ toxicity and the effects of YH439 were further evaluated using pyridine as a P450 2E1 inducer. Pyridine pretreatment substantially enhanced the $CCl_4$ hepatotoicity by 23-fold, relative to $CCl_4$ alone. YH439, however, failed to reduce the pyridine-potentiated toxicity, suggesting that the other form(s) of cytochroms P450 inducible by pyridine, but not suppressible by YH439 treatment, may play a role in potentiating $CCl_4-induced$ hepatotoxicity. YH439 was capable of blocking cadmium chloride-induced liver toxicity in mice. These results demonstrated that YH439 efficiently blocks Vit-A-enhanced hepatotoxiciy through Kupffer cell inactivation and that the suppression of P450 2E1 expression by YH439 is highly associated with blocking of propyl sulfide-mediated hepatotoxicity.

• The Korean Journal of Pharmacology
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• v.32 no.1
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• pp.75-82
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• 1996

The hypothesis that calcium provoke $O_2^-$ formation by Kupffer cells and may contribute to carbon tetrachloride $(CCl_4)$ induced liver injury was studied in SD rats. In $CCl_4-treated$ animals, hepatic malonaldehyde (nmole/gm liver) and plasma ALT (IU/ml) levels elevated significantly from $119.63{\pm}13.00$ to $268.97{\pm}14.82$ and from $17.3{\pm}0.18$ to $806.08{\pm}37.63$, respectively, compared to those in controls. Activation of Kupffer cells with high dose of retinol (250,000 IU/kg/day, po, for 7 day) significantly enhanced ALT levels, while inactivation of Kupffer cells with gadolinium chloride (7.5 mg/kg/day, ip, for 2 day) attenuated the increase of serum ALT level following $CCl_4$ treatment. Diltiazem (10 mg/kg/day, ip for 2 day) given in combination with retinol led to a marked decrease in ALT levels compare to the level in rats treated only with retinol against $CCl_4$ treatment. In order to determine any alterations in cytochrome P450 activities, the P450 content and the CYP2E1 activity were measured and all $CCl_4-treated$ rats showed significantly lower levels compared to those in controls and vehicle-treated animals. There were significant increases in glutathione peroxidase in all $CCl_4-treated$ rats except diltiazem treated groups. No difference was found among untreated and vehicle-treated rats. It is concluded that Kupffer cells contribute to $CCl_4-induced$ liver injury and that calcium antagonist attenuated the increased $CCl_4-induced$ liver injury due to activation of Kupffer cells.

• Biomolecules & Therapeutics
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• v.4 no.1
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• pp.89-96
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• 1996

The effect of Cimicifuga heracleifolia on CC1$_4$-induced hepatotoxicity was investigated. Cimicifuga heracleifolia has been used to diaphoresis, antipyretics and detoxification in oriental remedy. We examined the effect of Cimicifuga heracleifolia methanol extract by blood chemical analysis and histopathologic examination. ALT and AST were decreased by 38% and 67% in pretreatment group of Cimicifuga heracleifolia compared to CC1$_4$control group respectively. There were significant changes neither in total protein, albumin, triglyceride and cholesterol nor in BUN and creatinine. In histopathologic examination, there were severe necrosis and hemorrhage with infiltration of inflammatory cells around the central vein, zone 3 in the liver of CC1$_4$ treated rat. Ballooning degeneration of hepatocytes were frequently noted in the periphery of the hemorrhagic necrosis. In Cimicifuga heracleifolia pretreatment group, we observed mild degree of ballooning degeneration and inflammatory cell infiltration. No gross necrosis was observed. We measured malondialdehyde (MDA) formation by TBA method. It showed that the formation of MDA in Cimicifuga heracleifolia pretreatment group was decreased compared to the $CCl_4$control group. We got the result of the effect of Cimicifuga heracleifolia on CC1$_4$-induced hepatotoxicity by decreasing serum ALT and AST. It seems that the decrease of lipid peroxidation is related to the recovery effect.

• Journal of Life Science
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• v.15 no.4 s.71
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• pp.572-577
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• 2005

In this study, the effect of Epimedii Herba (EH) on the antioxidative enzymatic activity was investigated. EH (100mg/kg) was intraperitoneally administered into rats for 2 weeks. On the last day, carbon tetrachloride $(50\%\;CCl_4,\;3.3ml/kg,\;i.p.)$ dissolved in olive oil was injected before 12 hours. EH-pread-ministered and $CCl_4-treated$ (EC) group showed higher inhibitory effect in aminotransferase (AST, ALT) activity compared to $CCl_4-treated (CT)$ group. Superoxide dismutase (SOD) and Catalase in EC group were increased compared to those of CT group. The activity of glutathione peroxidase (GPx) was significantly higher than those of CT group compared to EC group. These results suggest that EH has a hepatoprotective effect through scavenging the free radicals induced by $CCl_4$.

• Journal of the Korean Applied Science and Technology
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• v.27 no.3
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• pp.290-299
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• 2010

The bioactive effects of ethanol extracts from fly maggot (ME) on reduction of plasma lipids levels in rats fed high-fat diets (Expt. Ⅰ), and on liver function recovery of hepatotoxicity rats by intraperitoneal injection of carbon tetrachloride ($CCl_4$) or by orally administration of alcohol (Expt. II) were investigated. In expt. I, twenty seven, male rat SDS(sprague dawley strain) were randomly assigned to three treated groups, including normal control group, HF (group with high fat diets which have no extracts) and HFE (HF plus orally administered doses of ME extract at 5.0 mg/100g of body weight). In expt. II, forty five, male rats (SDS) were randomly assigned to each of the five groups: T1 (control), T2 (intraperitoneal injection of $CCl_4$), T3 (intraperitoneal injection of $CCl_4$ after orally administered with ME), T4 (orally administered with combination of ME and alcohol), T5 (orally administration of ME after orally administered with alcohol). There were significant decreases in plasma (TAG), (TC), (LDL-C) in the HFE group with orally administered doses of ME at 5.0 mg/100g of body weight, respectively, however, the (HDL-C) were significantly increased in HFE group as compared to HF group with high fat diets which have no extracts (p<0.05). The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), ${\gamma}$-glutamyl transferse(${\gamma}$-GTP) and bilirubin were highest in T2 or T3, and high in order T4 or T5, and lowest in T1 except for bilirubin which has same with T4, T5 (p<0.05). The high recovery of liver damage by $CCl_4$ from the light microscopic appearance was observed in rats (T3) with extracts, and also high in T4 than T5 by orally administrated with alcohol. In conclusion, the ethanol extracts from fly maggot may have a bioactive effects to prevent for human lipids disorder and alcoholic disease.

• Korean Journal of Food Science and Technology
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• v.41 no.1
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• pp.93-99
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• 2009

This study aimed to determine whether or not glycoprotein isolated from Cudrania tricuspidata Bureau fruit(CTB glycoprotein) exerts a hepatoprotective effect on liver injury induced by the administration of carbon tetrachloride($CCl_4$, 1.0mL/kg) to A/J mice. Following the administration of CTB glycoprotein(0-20mg/kg), the activities of antioxidant enzymes (superoxide dismutase(SOD), catalase(CAT), and glutathione peroxidase(GPx)), and the quantities of measured thiobarbituric acid reactive substances(TBARS), lactate dehydrogenase(LDH), and nitric oxide(NO) were evaluated from the murine liver tissues and plasma. Additionally, the activity of nuclear factor-kappa B(NF-${\kappa}B$) was assessed after pretreatment with $CCl_4$. When the mice were treated with $CCl_4$ alone, the activities of antioxidative enzymes reduced but amounts of TBARS, LDH, and NO increased. However, the results of treatment with CTB glycoprotein(10 and 20 mg/kg) revealed significantly increased activities of antioxidant enzymes(SOD, CAT, and GPx), as compared with $CCl_4$ alone. On the other hand, the result showed significant diminutions of the quantities of TBARS, LDH, and NO after treatment with CTB glycoprotein(10 and 20 mg/kg), as compared to $CCl_4$ alone. The activity of NF-${\kappa}B$ also declined after pretreatment with CTB glycoprotein, as compared with $CCl_4$ treatment alone. Thus, it is suggested that the CTB glycoprotein exerts a protective effect against $CCl_4$-induced liver injury in A/J mice.

• YAKHAK HOEJI
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• v.34 no.4
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• pp.267-276
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• 1990

To achieve a better understanding of antioxidant action manifested by malotilate, the dithiol malonates, we monitored the oxy radical-scavenging system against the chronic hepatic damage induced by $CCl_4$ alone or in combination with ethanol. Malotilate was given orally at a dose of 100 mg/kg/day and $CCl_4$ 1.5 ml/kg was injected subcutaneously twice a week for 4 weeks. In each group receiving ethanol, drinking water was replaced by 20% aqueous solution or glucose, isocaloric amounts of ethanol, as a control of ethanol was diluted in its drinking water. Each rat was killed as a starved state at 18 hours after the period of the experiment, four weeks. The results were summarized as follows: 1) Malotilate inhibited the rate of generation of superoxide radicals, the accumulation of lipoperoxides, and promoted the synthesis of glutathione in the liver. 2) Malotilate stimulated the enhancement of activity of superoxide dismutase in hepatic mitochondria. 3) Malotilate had no effects on the hepatic $H_2O_2$ contents. 4) Malotilate showed the increase of catalase activity in the liver poisoned with $CCl_4$, and also gave a tendency to increase it in the liver intoxicated with ethanol. Thus, our data suggested that the activation of hepatic antioxidant system in the presence of malotilate would play a role in protecting liver against the toxic effects of oxy radical and/or lipid peroxides under the hepatotoxic conditions induced by $CCl_4$ with or without ethanol. However, the effects of malotilate against the ethanol-induced hepatotoxicity appear to be insignificant.