• 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.

• Natural Product Sciences
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• v.9 no.2
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• pp.87-90
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• 2003

The purpose of this study was to find the effect of 36 traditional medicinal plant species on hepatoprotective activity screening. For this study, carbon tetrachloride $(CCl_{4})$ intoxificated rats were used. Test extracts were made with the traditional medicinal plants refluxed in 95% MeOH and orally administered to the rats. Sixteen species, such as Mentha arvensis, Sophora japonica, Benincasa hispida, Lonicera japonica (Lonicerae Flos), Agaricus blazei, Epimedium koreanum, Aralia continentalis, Lithospermum erythrorhizon, Cimicifuga foetida, Gastrodia elata, Sanguisorba officinalis, Cephalonoplos segetum, Bupleurum falcatum, Alisma plantago-aquatica var. orientale, Lonicera japonica (Lonicerae Folium) and Sinomenium acutum showed protective effect against increased serum alanine aminotransferase (ALT) and/or serum asparteate aminotransferase (AST) activities.

• Korean Journal of Pharmacognosy
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• v.33 no.1 s.128
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• pp.5-12
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• 2002

This study was performed to evaluate hepatoprotective effect of Daewhang-whangryunhaedok-Tang(DWT) on liver injured rats induced by $CCl_4$ and the acute oral toxicity of it in mice. The activities of serum transaminase(ALT/AST), alkaline phosphatase(ALP) and lactic dehydrogenase (LDH), the levels of serum total cholesterol(TC) and triglyceride(TG), change of liver enlargement, and inhibitory activities of lipid peroxidation, catalase and glutathione-S-transferase(GST) in liver microsome were determined in hepatotoxic rats induced by $CCl_4$ DWT DWT was significantly reduced the serum ALT, AST, ALP, LDH, TC and TG levels. And, the increase of lipid peroxidation, decrease of catalase and GST activities in the liver microsome of $CCl_4$-intoxicated rat were significantly improved by the treatment of DWT. Male and female mice were administered maximum dosages of 5,000 mg/kg b.w. of DWT. After single oral administration of DWT to mice, we observed them daily for 2 weeks. DWT did not induce any toxic signs in the mortalities, clinical signs, body weight changes, and gross necropsy findings of mice. Based on these results, it is concluded that DWT may have the hepatoprotective effect on $CCl_4$ induced hepatotoxicity in rats. Also, DWT may have no side effect and its $LD_{50}$ value may be over 5,000 mg/kg b.w. in mice.

• Korean Journal of Pharmacognosy
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• v.17 no.2
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• pp.148-152
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• 1986

The preventive effect of Sosiho-Tang extract administered concurrently with methionine on hepatotoxicity induced by carbon tetrachoride (20% $CCl_4$ in olive oil, 5 ml/kg) in rats was studied. S-GOT values were decreased significantly by the concurrent administration of Sosiho-Tang extract 100 mg/kg with methionine 100 mg/kg and also Sosiho-Tang 200 mg/kg with methionine 100 mg/kg. S-GPT values were decreased remarkably by the concurrent administration of Sosiho-Tang extract 200 mg/kg with methionine 100 mg/kg. In histological observations, the pattern of the contrast group indicated the marked necrosis of the parenchymatous cells around the centrilobular area and the fatty changes of the hepatic cells around the midzonal area, but the concurrent administration of Sosiho-Tang extract 200 mg/kg and methionine 100 mg/kg revealed better improvements than their respective single administration in all pathological aspects.

• YAKHAK HOEJI
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• v.43 no.2
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• pp.198-207
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• 1999

The aim of the present investigation was to examine whether YH439, a hepatoprotective agent, exerts protective effect against hepatotoxicity and reduces the production of cytokines and NO in lipopolysaccharide (LPS)-primed rats with carbon tetrachloride ($CCl_4$). Administration of LPS following a single dose of CCl4 injection resulted in remarkable elevations of the serum $TNF{\alpha},{\;}IL-l{\beta$ and IL-6 level. The serum NO level was moderately elevated and severe liver damage was evidenced by increases in serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities. YH439 decreased the levels of TNF, $IL-l{\beta}$, IL-6, ALT, SDH as well as NO in the serum elevated by CCl4+LPS in a dose-dependent manner. Inducible nitric oxide synthase (iNOS) level was decreased in the liver of rats treated with YH439. The increased iNOS activity induced by LPS and $interferon-{\gamma}$ was significantly decreased in RAW 264.7 cells by YH439 treatment. YH439 increased the GSH level decreased by $CCl_4+LPS$ and suppressed the ratio of GSSG/GSH. The reduction of hepatotoxicity by YH439 may associated with the decrease in the production of cytokines as well as suppression of iNOS protein in conjunction with an increase in the GSH level.

• Journal of Yeungnam Medical Science
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• v.8 no.2
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• pp.84-94
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• 1991

The purpose of this study was to evaluate the influence of high does carbon tetrachloride($CCl_4$) on the hepatotoxic effect of dimethylnitrosamine(DMN) which induces acute hemorrhagic necrosis in liver. Rats were injected intraperitoneally DMN dissolved in physiologic saline by a dose of 40mg/kg. For changes related to $CCl_4$ pretreatment, rats were injected intraperitoneally $CCl_4$ dissolved in olive oil by a dose of 0.4mg/kg, and then injected DMN. The livers were extracted from the rats 3, 6, 12, 24, 48, 72, and 120 hours after $CCl_4$ and/or DMN injection. Liver tissues were examined with light and electron microscopes. The results were summarized as follows ; Light microscopic findings : Severe centrilobular hemorrhagic necrosis developed from 12 hours after injection of DMN and continued to 120 hours. On injection of DMN after $CCl_4$ pretreatment, Massive necrosis occurred early. But active regenerative changes were produced in 24 hours. In 120 hours, the liver recovered in almost normal appearance. The degree of necrosis in pretreated group was similar to that in DMN injection only, and the time of recovery was faster in preteated group. Electron microscopic findings ; The early change was mainly disorganization of RER in DMN injection, and clumping and vesicular dilatation of ER in injection of $CCl_4$. In pretreatment group the early change was similar in appearance with $CCl_4$ group, but severer in degree. According to the results, it was revealed that acute toxic effect of DMN was recovered more rapidly in pretreatment group. Thus it was suggested that $CCl_4$ had protective effect in DMN hepatotoxicity.

• Korean Journal of Clinical Laboratory Science
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• v.36 no.1
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• pp.55-63
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• 2004

The hepatotherapeutic effect of the extract of Lycii fructus has been studied in rats against $CCl_4$ induced liver toxicity. The rats were orally treated with $CCl_4$ (corn oil/$CCl_4$ 1:1, $1m{\ell}/kg$) and then $CCl_4$ ($0.5m{\ell}/kg$) administered four times for 2 weeks. The extracts of L. fructus have been administered every day for 2 weeks after the last $CCl_4$ injection. The experimental groups consisted of negative control (G1), positive control ($CCl_4$ alone; G2), extract of L. fructus (50 mg/kg; G3, 100 mg/kg; G4, 200 mg/kg; G5), respectively. There was a significant decrement to G2 on the serum level of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in G5. Also, the content of thiobarbituric acid reactive substance, and phosphatidylcholine hydroperxidase, a marker of lipid peroxidation, in the liver were decreased significantly G5 and G4 compared with G2. Although, catalase or superoxide dismutase, antioxidant enzyme, in the liver were decreased significantly too, it would not be a good sign for the liver. In histopathological findings, such a hepatocellular vacuolar degeneration, lobular restructure, cellular infiltration, necrosis, and so on were shown severely in G2. However, G4 and G5 was shown a mild cytoplasmic vacuolation and inflammatory cell. In conclusion, as a protection against cell damage, lipid peroxidation and serum level, it suggested that the extract of Lycii fructus would have been a therapeutic effect of liver injury directly.

• Journal of the Korean Society of Food Science and Nutrition
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• v.35 no.10
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• pp.1349-1355
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• 2006

This study was conducted to investigate the effect of methanol extract of Allomyrina dichotoma larva (MEAL) on carbon tetrachloride $(CCl_4)-induced$ hepatotoxicity in mice. ICR mice were divided into 5 groups [Vehicle control, $CCl_4\;(10{\mu}g/g)$ alone, $CCl_4$ plus a low dose $(50{\mu}g/g)$ of MEAL, $CCl_4$ plus a high dose $(100{\mu}g/g)$ of MEAL]. Silymarin $(2{\mu}g/g)$ was used as the reference in the experiment. Administration of MEAL tended to decrease the serum alanine transaminase (ALT) activity induced by $CCl_4$ treatment in mice. Hepatic concentration of thiobarbituric acid-reactive substances (TBARS) in a high-dose group of diet decreased to the level of silymarin-treated group. Hepatic activity of glutathione S-transferase in MEAL-treated group was lower than that of $CCl_4-treated$ group. Serum concentration of bilirubin was significantly increased by $CCl_4$ treatment, but MEAL or silymarin recovered the level. These results suggest that MEAL may exert the protective effect against $CCl_4-induced$ hepatotoxicity in mice. However, more intensive studies would be needed to elucidate the protective mechanism of the beetle on hepatotoxicity of mice.

• Journal of Physiology & Pathology in Korean Medicine
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• v.16 no.4
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• pp.684-692
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• 2002

Cordyceps militaris has been known as a Chinese traditional medicine for the treatment of tuberculosis, asthma, kidney disease, debility and fatigue etc. This study was attempted to investigate the therapeutic effect of C. militaris extract on the cytotoxic activity of HepG2, human hepatocellular carcinoma cells and the liver damage induced by carbon tetrachloride in SD rats. C. militaris extracts inhibited significantly the proliferation of HepG2 cells in vitro. Carbon tetrachloride(CCl₄) caused a significant an increase in liver weight, serum aspartate aminotransferase(AST) and alanine aminotransferase(ALT) activity, alkaline phosphatase(ALP), serum thiobarbituric acid reactive substances (TBARS), microsomal TBARS, and decrease in microsomal detoxification enzymes (cytochrome P-450, P-450 reductase, cytochrome b5, b5 reductase). TBARS and ALP in serum pretreated with C. militaris extracts (300mg/kg/day, 600mg/kg/day) was significantly reduced compared to control group(CCl₄). Cytochrome b5 and b5 reductase activities were significantly increased in CM300 (300 mg/kg/day) and CM600 group(600 mg/kg/day), and cytochrome P-450 reductase was significantly increased in CM300 group. Pretreatment (100, 300, and 600 mg/kg/day for 7 days) of C. militaris with CCl₄ was significantly inhibited the accumulation microsomal TBARS and the significantly increased in the cytochrome P-450 activity. These results suggested that C. militaris (300mg/kg/day for 7 days) has appreciable therapeutic effect on CCl₄ induced hepatotoxicity.

• Korean Journal of Veterinary Research
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• v.51 no.4
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• pp.259-265
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• 2011

Several compounds and extracts isolated from a brown alga, Ishige (I.) okamurae, exhibit anti-oxidant and anti-inflammatory effects. The present study investigated whether the ethyl acetate (EtOAc) fraction of I. okamurae (EFIO) could ameliorate carbon tetrachloride ($CCl_{4}$)-induced hepatotoxicity in rats. Sprague-Dawley rats were intraperitoneally (i.p.) administered with EFIO at 10 or 50 mg/kg per day for 2 consecutive days before $CCl_{4}$ injection (3.3 mL/kg, i.p.). Twenty four hours later, the rats were anesthesized with diethyl ether and dissected. Pretreatment with EFIO significantly reduced the increased serum levels of alanine aminotransferase and aspartate aminotransferase in $CCl_{4}$-treated rats. Pretreatment with EFIO also significantly inhibited the reduced activities of superoxide dismutase and catalase in the $CCl_{4}$-injured liver. Histopathological evaluations showed that hemorrhage, hepatocyte necrosis, inflammatory cell infiltration, and fatty degeneration induced by $CCl_{4}$ treatment were ameliorated by the administration of EFIO. Additionally, liver immunohistochemical analyses revealed the marked reduction in ED1-positive monocyte-like macrophages in EFIO-pretreated rats given $CCl_{4}$. These results suggest that EFIO ameliorates $CCl_{4}$-induced liver injury, possibly through the inhibition of oxidative stress.