• 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.

• Korean Journal of Veterinary Research
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• v.52 no.4
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• pp.275-280
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• 2012

The kiwi (Actinidia deliciosa) is well known to contain anti-oxidants. In this study, we investigated the anti-oxidant effects of kiwi extract on carbon tetrachloride ($CCl_4$) induced liver injury in BALB/c mice. The radical scavenging effect of 80% methanol extract of Halla-Gold kiwi was observed. For the animal study, mice were randomly divided into four groups: normal group, $CCl_4$-induced model group, kiwi extract administered group, and silymarin treated group. The kiwi extract was provided daily for 10 days. At the 24 h after last administration, $CCl_4$ was injected. The kiwi extract showed strong inhibitory effect of DPPH radicals and superoxide scavenging. In animal study, administration of $CCl_4$ resulted in significantly elevated plasma levels of ALT and AST but they decreased in kiwi-extract pretreated group. Anti-oxidant enzymes such as GSH-px and GSH-rd were restored in the kiwi extract treatment group. Histopathological degeneration was also prevented in the kiwi extract treated group compared with of the control group, which exhibited $CCl_4$-induced hepatotoxicity. On the basis of the obtained results, it can be concluded that kiwi extract showed protective effects, not only as anti-oxidant effects, but also in the protection of hepatotoxicity in $CCl_4$-intoxicated mice.

• Korean Journal of Pharmacognosy
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• v.36 no.1 s.140
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• pp.44-49
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• 2005

The protective effects of the DWP-04 [DDB : selenium yeast: glutathione {31.1 : 6.8 : 62.1 (%, w/w)} against hepatotoxicity by carbon tetrachloride $(CCl_4)$ were studied in rats. The rats were intraperitoneally injected with $CCl_4$ (50% in com oil) at initial dose of 1 ml/kg followed by 0.5 ml/kg 3 times during 1 week. The DWP-04 (50, 100 or 200 mg/kg) or its vehicle was administered everyday before the start of $CCl_4$ injection for two weeks. $CCl_4$ induced hepatocelluar degeneration and necrosis, which led to a great increase in serum aminotransferase, alkaline phosphatase activity and serum lipid levels. It was found by biochemical analysis that $CCl_4$ treatment remarkably increased thiobarbituric acid reactive substances and physphatidylcholine hydroperoxide in hepatic tissues and induced antioxidant enzymes such as catalase and superoxide dismutase (SOD). Liver and serum lipids were significantly lower in rats fed on DWP-04 than in rats induced by $CCl_4$ only-treatment. These results suggested that the DWP-04 could be a promising candidate for the protection of liver injury based on the preventive effects against lipid peroxidation and serum biochemical parameters.

• Korean Journal of Pharmacognosy
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• v.20 no.2
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• pp.96-100
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• 1989

Traditional herbal drugs of Korea, namely, Atractylodes Rhizome(蒼朮) and Atractylodes Rhizome White(白朮) which are derived from and old-grown rhizome and a newly-grown rhizome of Atractylodes japonica Koidz.(Compositae), respectively, were investigated their potential liver-protective activities against hepatotoxicity induced by $CCl_4$ intoxication in mice. Each herbal drug was extracted separately with chloroform, methanol and butanol. No extract of Atractylodes Rhizome showed a significant reduction of the duration of hypnosis produced by hexobarital after $CCl_4$ intoxication in mice. In addition, the the treatments of Atractylodes Rhizome extracts produced no decrease of aspartate aminotransferase(EC 2.6.1.1) activity in serum. However, the methanol extract of Atractylodes Rhizome White exhibited a marked protection from hepatotoxicity induced by $CCl_4$ intoxication in mice. It produced significant reductions of the duration of hypnosis and serum enzyme activity, but no other extract showed liver-protective activity against $CCl_4-induced$ hepatotoxicity.

• Environmental Analysis Health and Toxicology
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• v.23 no.4
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• pp.325-335
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• 2008

The protective effects of the Naringin, on carbon tetrachloride ($CCl_4$)-induced hepatotoxicity and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with Naringin prior to the administration of $CCl_4$ significantly prevented an increase in serum alanine, aspartate aminotransferase activity and hepatic lipid peroxidation in a dose-dependent manner. In addition, pretreatment with Naringin also significantly prevented the depletion of glutathione (GSH) content in the livers of $CCl_4$-induced mice. However, reduced hepatic glutathione levels was unaffected by treatment with Naringin alone. In addition, Naringin prevented $CCl_4$-induced apoptosis and necrosis, as indicated by a liver DNA laddering. To determine whether caspase-8,-3 pathway involved in $CCl_4$-induced acute liver injury, caspase-8, -3 activities were tested by ELISA. Naringin attenuated $CCl_4$induced caspase-8, -3 activities in mouse livers. $CCl_4$-induced hepatotoxicity was also prevented, as indicated by a liver histopathologic study. The effects of Naringin on the cytochrome P450 (CYP) 2E1, the major isozyme involved in $CCl_4$ were also investigated. Treatment of mice with Naringin resulted in a significant decrease of the CYP2E1-dependent hydroxyl at ion and aniline in a dose-dependent manner. These findings suggest that protective effects of Naringin against the $CCl_4$-induced hepatotoxicity may be due to its ability to block CYP2E1-mediated $CCl_4$ bioactivation and that is also protects against caspase-8, -3 pathway mediated apoptosis.

• Toxicological Research
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• v.11 no.2
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• pp.181-185
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• 1995

To know the mechanism of biphenyl dimethyl dicarboxylate (DDB) in the protection of chemically induced hepatotoxicity, the activity of glutamic pyruvic tran.saminase (GPT) and the level of lipid peroxidation metabolite (malondialdehyde, MDA) and ATP content in hepatocytes were determined in serum and primarily cultured hepatocytes. For in vibo study, rats were pretreated with DDB (300 mg/ kg, p.o.)for 7 days. DDB pretreatment efficiently reduced the elevation of serum GPT activity induced by carbon tetrachloride (1.6 ml/kg, s.c.) and acetaminophen administration (1500 mg/kg, i.p.). In ex vivo study, hepatocytes were isolated from the rats pretreated with DDB (300 mg/kg, p.o.)for 7 days and cultured for 12 hrs before inducing cytotoxicity with chemicals. The MDA formation and the GPT release induced by adriamycin $(1\times10^{-4} mg/ml)$ and cisplatin $(2\times10^{-4} mg/ml)$ were markedly decreased in the hepatocytes from the rats pretreated with DDB as compared to vehicle only. However, DDB pretreatment did not prevent the decrease of ATP contents of hepatocytes induced by cisplatin and adriamycin. In in vitro experiment, DDB was pretreated in primary cultured hepatocytes for 3 days. DDB enhanced the decreases of ATP contents induced by cisplatin and adriamycln. These results suggest that DDB may protect the hepatocytes from injury induced by hepatotoxlcants through inhibiting the lipid peroxidation.

• Journal of Haehwa Medicine
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• v.9 no.1
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• pp.135-142
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• 2000

For the evaluation of protective effect on hepatic damage by Korean red ginseng mixed formula, we used GR(Korean red ginseng), GRF-A(Korean red ginseng-mixed formula) as a materials. The study was performed on protective effect against hepatic damage induced by $CCl_4$. In vitro assay with 1.1 mM galactosamine, protection(%) was 44%(GR), 58%(GRF-A) at 50ug/ml, while maxium protection(%) was 5%(GR) and 24% (GRF-A) against acute hepatotoxicity by $CCl_4$. GRF-A significantly protected ethanol induced-liver damage by lowering ALT and ALP and fatty degenertion in liver tissue.

• Journal of Life Science
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• v.20 no.1
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• pp.133-141
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• 2010

The protective effect of a mixed powder from solid-cultured and liquid-cultured Lentinus edodes mycelia (2:1, w/w) (designate LED) on the carbon tetrachloride ($CCl_4$)- and ethanol-induced hepatotoxicity of male Sprague-Dawley (SD) rat was investigated. In the $CCl_4$-induced rat hepatotoxicity experiment, rats of 4 groups (6 rats/group) were administere with Normal (0.2 ml distilled water), Control (0.2 ml distilled water), LED (LED 200 mg/kg BW + 0.2 ml distilled water), and Silymarin (200 mg/kg BW + 0.2 ml distilled water), p.o., daily for 2 weeks. Afterwards, all groups except for the Normal group were subjected to abdominal injection with $CCl_4$ ($CCl_4$ : corn oil, 1:1 v/v; 0.5 ml/kg BW). For the ethanol- induced rat hepatotoxicity experiment, rats were divided into 5 groups (5 rats/group): Normal; Pair-fed control (PFC); Control (ethanol); LED (ethanol + LED 200 mg/kg BW); and Silymarin (ethanol + silymarin 200 mg/kg BW). Rats of the Normal and PFC groups were fed a basal liquid diet, and rats of the Control, LED, and Silymarin groups were fed a liquid ethanol diet containing LED or Silymarin. Eight weeks later, blood and liver samples were collected to analyze biomarkers. In $CCl_4$-induced SD rats, LED elevated hepatic superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH peroxidase) activities and thiobarbituric reactive substances (TBARS) were reduced, resulting in the reduction of glutamate-oxalate transaminase (GOT), glutamate-pyruvate transaminase (GPT) and lactic dehydrogenase (LDH) activities in plasma. Similar results of these enzymes and biochemical markers in both liver tissues and plasma were seen in ethanol-induced hepatotoxicity of SD rats. In addition, elevated alcohol dehydrogenase (ADH) activity and reduced expression of cytochrome p450 mixed monooxygenase enzyme (CYP2E1) were seen in liver tissues from ethanol-treated rats by LED treatment. These effects of LED were similar to those of Silymarin. In in vitro experiments, LED showed antioxidant activity in a 2,2-diphenyl-1-picrylhydrazyl (DPPH) system and mouse liver mitochondria system induced by NADPH/$Fe^{2+}$ and cumine hydroperoxide (CuOOH). These results indicate that LED protected SD rat hepatotoxicity, induced by $CCl_4$ and ethanol, through its antioxidative activity and might be useful as a material for protection from hepatoxicity in humans.

• Food Science and Biotechnology
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• v.17 no.1
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• pp.203-207
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• 2008

The present study aimed at assessing the protective effect of water extract from fruit body of the Grifola frondosa (GFW) on carbon tetrachloride ($CCl_4$)-induced hepatotoxicity. Rats orally administered with GFW 0.5, 1.0, 2.0 g/kg for 14 days were treated with $CCl_4$ to induce hepatotoxicity. Pretreatment with GFW remarkably prevented the elevation of serum AST, ALT, ALP, LDH, $\gamma$-GTP, and liver lipid peroxides in $CCl_4$-treated rat and GFW administration in liver injured rats by $CCl_4$ showed significant (p<0.05) protection of liver as evidenced from normal serum enzymes and malondialdehyde (MDA) levels. In the ultrastructural changes, administration of $CCl_4$-induced damage of hepatocytes with vacuolation, a highly damaged endoplasmic reticulum, and degenerating nuclei. However, pre-administration with GFW preserved normal ultrastructure of hepatocytes. These results suggest that GFW had an effect to inhibit $CCl_4$-induced liver injury in rat, and that it could be used as an effective hepatoprotective agent against chemical-induced liver damage.

• Bulletin of the Korean Chemical Society
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• v.27 no.9
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• pp.1386-1392
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• 2006

Kahweol and cafestol significantly reduced t-BHP-induced oxidative injuries in cultured rat hepatocytes, as determined by cell cytotoxicity, intracellular glutathione (GSH) content and lipid peroxidation in a dose-dependent manner. In addition, kahweol and cafestol provided good protection from the t-BHPinduced production of intracellular reactive oxygen species and DNA damage. The in vivo study showed that pretreatment with kahweol and cafestol prior to the administration of t-BHP significantly prevented the increase in serum levels of hepatic enzyme markers (alanine aminotransferase and aspartate aminotransferase) and reduced oxidative stress, such as GSH content and lipid peroxidation, in the liver in a dose-dependent manner. The histopathological evaluation of the livers also revealed that kahweol and cafestol reduced the incidence of liver lesions induced by t-BHP. Taken together, these results support the anti-oxidative role of kahweol and cafestol and demonstrate that kahweol and cafestol can protect hepatocytes from oxidative stress.