• Nutrition Research and Practice
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• v.5 no.6
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• pp.520-526
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• 2011

Folate deficiency and hyperhomocysteinemia are found in most patients with alcoholic liver disease. Oxidative stress is one of the most important mechanisms contributing to homocysteine (Hcy)-induced tissue injury. However it has not been examined whether exogenous administration of folic acid attenuates oxidative stress and hepatic toxicity. The aim of this study was to investigate the in vivo effect of folic acid supplementation on oxidative stress and hepatic toxicity induced by chronic ethanol consumption. Wistar rats (n = 32) were divided into four groups and fed 0%, 12%, 36% ethanol, or 36% ethanol plus folic acid (10 mg folic acid/L) diets. After 5 weeks, chronic consumption of the 36% ethanol diet significantly increased plasma alanine transaminase (ALT) (P < 0.05) and aspartate transaminase (AST) (P < 0.05), triglycerides (TG) (P < 0.05), Hcy (P < 0.001), and low density lipoprotein conjugated dienes (CD) (P < 0.05) but decreased total radical-trapping antioxidant potential (TRAP) (P < 0.001). These changes were prevented partially by folic acid supplementation. The 12% ethanol diet had no apparent effect on most parameters. Plasma Hcy concentration was well correlated with plasma ALT (r = $0.612^{**}$), AST (r = $0.652^*$), CD (r = $0.495^*$), and TRAP (r = $-0.486^*$). The results indicate that moderately elevated Hcy is associated with increased oxidative stress and liver injury in alcohol-fed rats, and suggests that folic acid supplementation appears to attenuate hepatic toxicity induced by chronic ethanol consumption possibly by decreasing oxidative stress.

• The Journal of Internal Korean Medicine
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• v.23 no.2
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• pp.222-227
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• 2002

Although there are a few reports concerning the side effects and toxicity of herbal medicines, there has not yet been any report concerning their causes, mechanisms or prevention. We investigated the internal reports concerning the side effects and toxicity of herbal medicines. In the findings, liver disorder (hepatic injury) was found in 7 cases, kidney disorders (nephropathy) were found in 12 cases, heart disorders were found in 4 cases and mineral-caused diseases were found in 2 cases. Besides, we found the major cause of the side effects and toxicity was drug abuse, such as over-dosage and long term medication. So, we hope this report brings more attention to the safety and toxicity of herbal medicines.

• Korean Journal of Pharmacognosy
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• v.16 no.4
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• pp.227-232
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• 1985

Gardenia jasminodes has been medically used for anti-inflammation, sedation and anti-diarrhea; The extract of this plant has been traditionally used as food colorant and referred as crocin dyes. In the present study, the possible hepatic toxicity of this dye has been evaluated on the basis of its alteration on the marker enzymes, namely, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, alkaline phosphatase, lactate dehydrogenase and gamma-glutamyltransferase. Crocin dyes did not affect hepatic function when they were orally administered to rats in a daily dose of 50 mg/kg for 8 days, but could induce acute hepatic discoloration. A high dose of 100 mg/kg for 2 weeks could induce both hepatic damage and black pigmentation, but a lower dose of 10 mg/kg for 40 days did not The induced black pigmentation and the acute hepatic damage were completely reversible. In conclusion, the crocin dyes have a very low hepatic toxicity in rats, even in high experimental dosages which could hardly happen in human practice. It is therefore suggested that the crocin dyes are safe for coloring foods.

• Nutrition Research and Practice
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• v.2 no.4
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• pp.195-199
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• 2008

Alcoholism has been associated with folate deficiency in humans and laboratory animals. Previous study showed that ethanol feeding reduces the dehydrogenase and hydrolase activity of 10-formyltetrahydrofolate dehydrogenase (FDH) in rat liver. Hepatic ethanol metabolism generates acetaldehyde and acetate. The mechanisms by which ethanol and its metabolites produce toxicity within the liver cells are unknown. We purified FDH from rat liver and investigated the effect of ethanol, acetaldehyde and acetate on the enzyme in vitro. Hepatic FDH activity was not reduced by ethanol or acetate directly. However, acetaldehyde was observed to reduce the dehydrogenase activity of FDH in a dose- and time-dependent manner with an apparent $IC_{50}$ of 4 mM, while the hydrolase activity of FDH was not affected by acetaldehyde in vitro. These results suggest that the inhibition of hepatic FDH dehydrogenase activity induced by acetadehyde may play a role in ethanol toxicity.

• Journal of Ginseng Research
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• v.37 no.1
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• pp.37-44
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• 2013

Korean red ginseng is known to regulate the immune system and help the body struggle infection and disease. Cadmium is widely distributed in the environment due to its use in industry. Exposure to cadmium is problematic causing organ dysfunction. This study was conducted to evaluate the protective effect of Korean red ginseng extract (RGE) against cadmium-induced hepatotoxicity in rats. In experiments, animals were orally administrated with RGE (25, 50 mg/kg) for 7 d and then intravenously injected with cadmium ($CdCl_2$, 4 mg/kg) to induce acute hepatotoxicity. Cadmium caused the elevated levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase in serum. In contrast, pretreatment with RGE significantly reduced those serum indexes related with liver damage. In histopathological analysis, RGE decreased the centrilobular necrosis around central veins and the peripheral hemorrhage around portal triads. Moreover, RGE restored the deficit in hepatic glutathione level resulting from cadmium treatment. RGE also inhibited the increase in the expression of Bad, a representative apoptosis marker protein, induced by cadmium treatment. Collectively, these results demonstrate that RGE can reduce the cadmium-induced hepatic toxicity, partly via anti-oxidative and anti-apoptotic process.

• Toxicological Research
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• v.13 no.3
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• pp.183-186
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• 1997

Acute toxicity of pectenotoxin 2 (PTX2) was examined in mice. Treatment of mice with a toxic dose of PTX2 resulted in clinical signs such as ataxia, cyanosis and an abrupt decrease in body temperature. Histopathological studies revealed that the liver is the major target organ for PTX2. Activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and sorbitol dehydrogenase (SDH) were significantly elevated by PTX2 administration. Glucose-6-phosphatase activities were not changed by the treatment. The PTX2 treatment decreased relative liver weight without changing the body weight. The effect of PTX2 on hepatic drug metabolizing enzyme system was determined. An ip dose of PTX2 (200 $\mu$g/kg) induced a significant decrease in the hepatic microsomal protein content. Cytochrome P-450 content, cytochrome b$_5$ content, NADPH cytochrome c reductase, aminopyrine N-demethylase activities, or hepatic glutathione content were not altered by PTX2 treatment.

• Korean Journal of Pharmacognosy
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• v.28 no.4
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• pp.280-285
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• 1997

Pectenotoxin 2 (PTX2), isolated from marine sponges, was examined for its hepatotoxic potential using male ICR mice. PTX2 $(20\;or\;100\;{\mu}g/kg/day,\;ip)$ was administered to mice repeatedly for one or two week. Histopathological examination revealed an increase in granularity in the liver from the mice treated with PTX2. PTX2 did not alter the parameters for hepatotoxicity and nephrotoxicity such as sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and blood urea nitrogen (BUN). Cytochrome P-450, cytochrome $b_5$, or NADPH cytochrome c reductase was net changed by repeated administration of PTX2. Hepatic microsomal activity of p-nitroanisole O-demethylase, but not aminopyrine N-demethylase, was slightly depressed by PTX2 administerd repeatedly $(100\;{\mu}g/kg/day,\;ip)$ fur 2 weeks. The toxicity of PTX2 $(200\;{\mu}g/kg/day,\;ip)$ was determined in mice pretreated with a metabolic inducer or inhibitor such as phenobarbital, 3-methyl-cholanthrene, $CoCl_2$, or SKF 525-A. Significant alterations in lethality and hepatotoxicity of PTX2 were observed in mice pretreated with a metabolic modulator. The results suggest that liver seems to be the target organ for PTX2 toxicity and also that induction of the PTX2 toxicity may be associated with hepatic drug metabolizing activity.

• Toxicological Research
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• v.29 no.3
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• pp.165-172
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• 2013

Acetaminophen (APAP) known as paracetamol is the main ingredient in Tylenol, which has analgesic and anti-pyretic properties. Inappropriate use of APAP causes major morbidity and mortality secondary to hepatic failure. Overdose of APAP depletes the hepatic glutathione (GSH) rapidly, and the metabolic intermediate leads to hepatocellular death. This article reviews the mechanisms of hepatotoxicity and provides an overview of current research studies. Pharmacokinetics including metabolism (activation and detoxification), subsequent transport (efflux)-facilitating excretion, and some other aspects related to toxicity are discussed. Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated gene battery plays a critical role in the multiple steps associated with the mitigation of APAP toxicity. The role of Nrf2 as a protective target is described, and potential natural products inhibiting APAP toxicity are outlined. This review provides an update on the mechanism of APAP toxicity and highlights the beneficial role of Nrf2 and specific natural products in hepatoprotection.

• Toxicological Research
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• v.4 no.2
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• pp.107-115
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• 1988

The effects of altering the hepatic mixed-function oxidase(MFO) activities on the acute toxicity of parathion were examined in female rats. Phenobarbital sodium pretreatment (50mg/kg/day, i.p.) for 4 consecutive days has resulted in significant decreases in the toxicity of parathion (2 or 4 mg/kg, i.p.) as determined by lethality and cholinesterase activities wheras the toxicity arising from a single dose of CCl4(2 mmol/kg, i.p.) 24 hr prior to parathion challenge was potentiated.

• Toxicological Research
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• v.31 no.2
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• pp.137-149
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• 2015

Human hepatocytes, with complete hepatic metabolizing enzymes, transporters and cofactors, represent the gold standard for in vitro evaluation of drug metabolism, drug-drug interactions, and hepatotoxicity. Successful cryopreservation of human hepatocytes enables this experimental system to be used routinely. The use of human hepatocytes to evaluate two major adverse drug properties: drug-drug interactions and hepatotoxicity, are summarized in this review. The application of human hepatocytes in metabolism-based drug-drug interaction includes metabolite profiling, pathway identification, P450 inhibition, P450 induction, and uptake and efflux transporter inhibition. The application of human hepatocytes in toxicity evaluation includes in vitro hepatotoxicity and metabolism-based drug toxicity determination. A novel system, the Integrated Discrete Multiple Organ Co-culture (IdMOC) which allows the evaluation of nonhepatic toxicity in the presence of hepatic metabolism, is described.