• YAKHAK HOEJI
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• v.42 no.6
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• pp.598-606
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• 1998

The liver expresses a considerable amount of nitric oxide (NO) upon induction with cytokines or/and endotoxin. The NO synthesized by inducible NO synthase (NOS) of the liver see ms to play a role in various hepatic physiological processes. Here we investigate the effects of NO on acetaminophen (AA)-induced liver injury. The treatment of S-nitros-N-acetyl penicillamine (SNAP, exogenous NO donor) at the dose of 0.1mM decreased AA-induced hepatotoxicity suggesting the possibility of NO to play a role in protection from the hepatotoxicity induced by AA. On the other hand, the excessive NO produced by NO donor (SNAP: 0.5, 2.5, 6.25mM) has been shown to cause a concentration dependent hepatotoxicity, and such damages was decreased by Superoxide and increased by superoxide dismutase, indicating that the hepatotoxicity induced by excessive NO depends on balancing between NO and superoxide. Taken together, the results indicate that NO has biphasic effects on hepatotoxicity.

• Journal of Environmental Health Sciences
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• v.19 no.1
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• pp.66-70
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• 1993

Introduction : Methanethiol is a toxicant that is a byproduct in the industrial process (oil refinery), and it is produced in vivo from methionine via transamination in case of its overintake. And it also can be generated by the action of mucosal thiol Smethyltransferase on hydrogen sulfite which is formed by anaerobic bacteria in the intestinal tract. The toxicity of methanethiol has often been suggested as one of endogenous factors involved in the pathogenesis of hepatic encephalopathy. Furthermore, methanethiol could cause the membrane damage and inhibition of some membrane protective enzymes.

• Toxicological Research
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• v.33 no.4
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• pp.299-304
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• 2017

Thallium and its compounds are a class of highly toxic chemicals that cause wide-ranging symptoms such as gastrointestinal disturbances; polyneuritis; encephalopathy; tachycardia; skin eruptions; hepatic, renal, cardiac, and neurological toxicities; and have mutagenic and genotoxic effects. The present research aimed to evaluate the efficacy of the chelating agents deferasirox (DFX) and deferiprone (L1) in reducing serum and tissue thallium levels after the administration of thallium (III), according to two different dosing regimens, to several groups of Wistar rats for 60 days. It was hypothesized that the two chelators might be more efficient as a combined therapy than as monotherapies in removing thallium (III) from the rats' organs. The chelators were administered orally as either single or combined therapies for a period of 14 days. Serum and tissue thallium (III) and iron concentrations were determined by flame atomic absorption spectroscopy. Serum and tissue thallium (III) levels were significantly reduced by combined therapy with DFX and L1. Additionally, iron concentrations returned to normal levels and symptoms of toxicity decreased.

• Biomolecules & Therapeutics
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• v.7 no.1
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• pp.35-43
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• 1999

Hepatoprotective effects of Malloti cortex extract (MCE) from Mallotus japonicus against the carbon tetrachloride (CCl$_{4}$) and galactosamine (GalN) were investigated. Whereas serum aspartate aminotransferase and alanine aminotransferase levels were markedly elevated after CCl$_{4}$ and GalN administration, pretreatment and posttreatment with MCE before and after the injection of CCl$_{4}$ and GalN resulted in decreases in elevated serum aminotransferase activities. Whereas CCl$_{4}$ and GalN treatment caused 3~7 fold increases in sorbitol dehydrogenase and ${\gamma}$-glutamyltransferase activities, pretreatment and posttreatment with MCE resulted in the blocking of CCl$_{4}$ and GalN-induced liver toxicity. The hepatoprotective effect of MCE was in part due to MCE-induced elevation of hepatic glutathione levels. Pretreatment and posttreatment with MCE also reduced increased lipid peroxidation induced by CCl$_{4}$ and GalN. These results suggest that MCE may be useful for the prevention and therapy of hepatotoxic pathogenesis. It is presumed that protective and therapeutic effects of MCE due to be inducible glutathione S-transferase and glutathione reductase activities, involving in glutathione-medicated detoxication and maintainment of glutathione content, respectively.

• Mass Spectrometry Letters
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• v.13 no.4
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• pp.95-105
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• 2022

Amatoxin-induced mushroom poisoning starts with nonspecific symptoms of toxicity but hepatic damage may follow, resulting in the rapid development of liver insufficiency and, ultimately, coma and death. Accurate detection of amatoxins, such as α-, β-, and γ-amanitin, within the first few hours after presentation is necessary to improve the therapeutic outcomes of patients. Therefore, analytical methods for the identification and quantification of α-, β-, and γ-amanitin in biological samples are necessary for clinical and forensic toxicology. This study presents a literature review of the analytical techniques available for amatoxin detection in biological matrices, and established an inventory of liquid chromatography (LC) techniques with mass spectrometry (MS), ultraviolet (UV) detection, and electrochemical detection (ECD). LC-MS methods using quadrupole tandem mass spectrometry, time-of-flight mass spectrometry, and orbitrap MS are powerful analytical techniques for the identification and determination of amatoxins in plasma, urine, serum, and tissue samples, with high sensitivity, specificity, and reproducibility compared to LC with UV and ECD, enzyme-linked immunoassay, and capillary electrophoresis methods.

• Toxicological Research
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• v.32 no.1
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• pp.73-80
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• 2016

Chronic exposure to cadmium (Cd) is known to adversely affect renal function. Our previous studies indicated that Cd induces p53-dependent apoptosis by inhibiting gene expression of the ubiquitin-conjugating enzyme (Ube) 2d family in both human and rat proximal tubular cells. In this study, the effects of Cd on protein expression of p53 and apoptotic signals in the kidney and liver of mice exposed to Cd for 12 months were examined, as well as the effects of Cd on p53 protein levels and gene expression of the Ube2d family in various cell lines. Results showed that in the kidney of mice exposed to 300 ppm Cd for 12 months, there was overaccumulation of p53 proteins in addition to the induction of apoptosis, which was triggered specifically in the proximal tubules. Interestingly, the site of apoptosis was the same as that of p53 accumulation in the proximal tubules. In the liver of mice chronically exposed to Cd, gene expression of the Ube2d family tended to be slightly decreased, together with slight apoptosis without the accumulation of p53 protein. In rat small intestine epithelial (IEC-6) cells, Cd decreased not only the p53 protein level but also gene expression of Ube2d1, Ube2d2 and Ube2d4. In human brain microvascular endothelial cells (HBMECs), Cd did not suppress gene expression of the Ube2d family, but increased the p53 protein level. In human brain astrocytes (HBASTs), Cd only increased gene expression of UBE2D3. These results suggest that Cd-induced apoptosis through p53 protein is associated with renal toxicity but not hepatic toxicity, and the modification of p53 protein by Cd may vary depending on cell type.

• Journal of Life Science
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• v.34 no.4
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• pp.227-235
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• 2024

Hepatocyte damage caused by medications or herbal products is one of the important problem when these compounds are chronically administrated. Thus, improving hepatocyte survival during treatment offers a wide range of opportunities. Valproic acid (VPA), a branched short-chain fatty acid derived from naturally occurring valeric acid, is commonly used to treat epilepsy and seizures. Although VPA exerts numerous effects in cancer, HIV therapy, and neurodegenerative disease, its effects on the liver and its mechanism of action have not been fully elucidated. Here, we demonstrated that VPA caused moderate liver cell toxicity and apoptosis. Interestingly, VPA treatment increased transcription levels of PPAR alpha (PPAR-α) and fibroblast growth factor 21 (FGF21) in murine (Hepa1c1c7) hepatoma cells in a time and concentration dependent manner. VPA-induced FGF21 expression was significantly weaker under PPAR-α silencing condition than in cells transfected with non-targeting control siRNA. Subsequent experiments showed that cell viability was significantly lowered when the FGF21 signaling pathway was blocked by FGF receptor antagonist. Finally, we further determined that AMPK phosphorylation was not responsible for VPA-induced FGF21 expression and PPAR-a increments. These results indicate that increases of FGF21 expression alleviate VPA-induced hepatic toxicity, thereby making FGF21 a potential biomarker for predicting liver damage during VPA treatments.

• Journal of the Korean Society of Food Science and Nutrition
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• v.39 no.3
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• pp.343-349
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• 2010

The liver is the major target of ethanol toxicity and oxidative stress plays a role in development of alcoholic liver disease. This study was performed to investigate the effects of green tea extracts (GTE) on acute ethanol-induced hepatotoxicity in rats. Experimental animals were divided into 4 groups, control, GTE, ethanol, and GTE+ethanol treatment, with 5 rats in each group. Ethanol (6 g/kg body weight (BW)) and GTE (200 mg/kg BW) were treated by gavage. At 1 hour, 3 hours and 20 days (6 g/kg BW every 2 days for total 10 doses) after ethanol and/or GTE treatments, animals were killed; hepatic tumor necrosis factor-alpha (TNF-$\alpha$) and glutathione level, serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), hepatic antioxidant enzymes (SOD, CAT, GPx) activities and hepatic thiobarbituric acid reactive substances (TBARS) were measured. At 1 hour and 3 hours, hepatic TNF-$\alpha$ levels were increased significantly in ethanol group and ethanol+GTE group but that levels was significantly lower in ethanol+GTE group compared with ethanol group. Hepatic glutathione level was decreased by ethanol treatment but GTE prevented the ethanol-induced glutathione decrement. The levels of liver marker enzymes (AST, ALT), liver antioxidant enzymes (SOD, CAT, GPx) and lipid peroxidation marker (TBARS) were not changed in rats of 1 and 3 hours after ethanol treatment. After 20 days, GTE decreased the changes of liver marker enzymes (AST, ALT) activities and TBARS level by ethanol. This study shows that GTE beneficially modulates TNF-$\alpha$ and glutathione levels in liver of ethanol administered rats. The GTE supplementation could be beneficial to liver by decreasing early changes of biomarkers of liver damage caused by ethanol.

• Radiation Oncology Journal
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• v.13 no.4
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• pp.321-330
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• 1995

Purpose : To evaluate whether the early pulmonary irradiation can prevent or decrease the pulmonary damage and contribute to improve ultimate survival in paraquat lung. Materials and Methods : From Jun. 1987 to Aug. 1993, thirty patients with paraquat poisoning were evaluated. Fourteen of these patients were received pulmonary irradiation(RT). All of the patients were managed with aggressive supportive treatment such as gastric lavage, forced diuresis, antioxidant agents and antifibrosis agents. Ingested amounts of paraquat were estimated into three groups(A : minimal 50cc). Pulmonary irradiation was started within 24 hours after admission(from day 1 to day 11 after ingestion of paraquat). Both whole lungs were irradiated with AP/PA parallel opposing fields using Co-60 teletherapy machine. A total of 10Gy(2Gy/fr. x 5days) was delivered without correction of lung density. Results : In group A, all patients were alive regardless of pulmonary irradiation and in group C, all of the patients were died due to multi-organ failure, especially pulmonary fibrosis regardless of pulmonary irradiation. However, in group B, six of 7 patients($86{\%}$) with no RT were died due to respiratory failure, but 4 of 8 patients with RT were alive and 4 of 5 patients who were received pulmonary irradiation within 4 days after ingestion of paraquat were all alive though radiological pulmonary change. One patient who refused RT after 2Gy died due to pulmonary fibrosis. All 3 patients who were received pulmonary irradiation after 4 days after ingestion were died due to pulmonary fibrosis in spite of recovery from renal and hepatic toxicity Conclusion : It is difficult to find out the effect of pulmonary irradiation on the course of the paraquat lung because the precise plasma and urine paraquat concentration were not available between control and irradiation groups. But early pulmonary irradiation within 4 days after paraquat poisoning with aggresive supportive treatment appears to decrease Pulmonary toxicity and contribute survival in patients with mouthful ingestion of paraquat who are destined to have reversible renal and hepatic damage but irreversible pulmonary toxicity.

• Toxicological Research
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• v.14 no.3
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• pp.293-300
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• 1998

Previous studies have shown that the heterocycles including thiazoles are efficacious in inducing phase phase II metabolizing enzyme as well as certain cytochrome P450s and that the inductin of these matabolizing enzymes by the heterocyclic agents is highly associated with their hepatotoxicity. In the present study, the effects of benzylisothiazole (BIT), which has a isothiazole moiety, on the expression of microsomal epoxide hydrolase (mEH), major glutathione S-transerases and cytochrome P450s were studied in the rat liver in association with its hepatotoxicity. Treatment of rats with BIT(1.17 mmol/kg, 1~3d) resulted in substantial increases in the mEH. rGSTA2, rGSTA2, rGSTM1 and rGSTM2 mRNA levels, whereas rGSTA3 and rGSTA5 mRNA levels were increased to much lesser extents. A time-course study showed that the mRNA levels of mEH and rGSTs were greater at 24hr after treatment than those after 3 days of consecutive treatment. Relative changes in mEH and rGST mRNA levels were consistent with those in the proteins, as assessed by Western immunoblot analysis. Hepatic cytochrom P450 levels were monitored after BIT treatment under the assumption that metabolic activation of BIT may affect expression of the enzymes in conjunction with hepatotoxicity. Immunoblot analysis revealed that cytochrome P450 2B1/2 were 3-to 4-fold induced in rats teatd with BIT(1.17 mmol/kg/day.3days), whereas P450 1A2, 2C11 and 3A1/2 levels were decreased to 20~30% of those in unteatd rats. P450 2E1 was only slightly decreased by BIT. Thus, the levels of several cytochrome P450s were suppressed by BIT treatment. Rats treated with BIT at the dose of 1.17mmol/kg for 3 days exhibited extensive multifocal nodular necrosis with moderate to extensive diffuse liver cell degeneration. No notable toxicity was observed in the kidney. These results showed that BIT induces mEH and rGSTs in the liver with increases in the mRNA levels, whereas the agent significantly decreased major cytochrome P450s. The changes in the detoxifying enzymes might be associated with the necrotic liver after consecutive treatment.