• Bulletin of the Korean Chemical Society
• /
• v.28 no.6
• /
• pp.977-982
• /
• 2007

For the development of novel hepatoprotective agents, C2, C3, C23 and C28 functional groups on asiatic acid were modified, and the prepared compounds were evaluated for their hepatoprotective effects. Among the prepared compounds, 9, 13 and 16 showed significant hepatoprotective activities against CCl4- and galactosamine (GaIN)-induced hepatotoxicity. Especially, compound 9 showed the most significant hepatoprotective effects against GaIN-induced hepatotoxicity (66.4% protection at 50 μM) and moderate hepatoprotective activities against CCl4-induced hepatotoxicity (20.7% protection at 50 μM).

• Biomolecules & Therapeutics
• /
• v.26 no.6
• /
• pp.599-607
• /
• 2018

Fasiglifam (TAK-875) a G-protein coupled receptor 40 (GPR40) agonist, significantly improves hyperglycemia without hypoglycemia and weight gain, the major side effects of conventional anti-diabetics. Unfortunately, during multi-center Phase 3 clinical trials, unexpected liver toxicity resulted in premature termination of its development. Here, we investigated whether TAK-875 directly inflicts toxicity on hepatocytes and explored its underlying mechanism of toxicity. TAK-875 decreased viability of 2D and 3D cultures of HepG2, a human hepatocarcinoma cell line, in concentration-(>$50{\mu}M$) and time-dependent manners, both of which corresponded with ROS generation. An antioxidant, N-acetylcysteine, attenuated TAK-875-mediated hepatotoxicity, which confirmed the role of ROS generation. Of note, knockdown of GPR40 using siRNA abolished the hepatotoxicity of TAK-875 and attenuated ROS generation. In contrast, TAK-875 induced no cytotoxicity in fibroblasts up to $500{\mu}M$. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at$25{\mu}M$. Histopathological examination of zebrafish exposed to TAK-875 revealed severe hepatotoxicity as manifested by degenerated hypertrophic hepatocytes with cytoplasmic vacuolation and acentric nuclei, confirming that TAK-875 may induce direct hepatotoxicity and that ROS generation may be involved in a GPR40-dependent manner.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.12
• /
• pp.7427-7431
• /
• 2013

Aims: To examine the pretreatment effects of regular aerobic training on the IGF system (IGF-I, IGFBP-3 and IGF/IGFBP) and doxorubicin(DOX) induced hepatotoxicity in rats. Materials and Methods: Forty-eight male rats were divided into groups:(1) control+placebo (2) $control+DOX_{10}mg{\cdot}kg^{-1}$ (3) $control+DOX_{20}mg{\cdot}kg^{-1}$ (4) training+placebo (5) $training+DOX_{10}mg{\cdot}kg^{-1}$ (6) $training+DOX_{20}mg{\cdot}kg^{-1}$. Hepatotoxicity was induced by DOX with dosages of 10 and 20 $mg{\cdot}kg^{-1}$. The rats in groups 4, 5 and 6 performed treadmill running of 25-54 min/day and 15-20 m/min, 5 days/wk for 6 wks. At the end of the aerobic training protocol, rats in the 1 and 4 groups, in the 2 and 5 groups and in the 3 and 6 groups received saline solution, $DOX_{10}mg{\cdot}kg^{-1}$ and $DOX_{20}mg{\cdot}kg^{-1}$, respectively. Results: Administration of $DOX_{20}mg{\cdot}kg^{-1}$ caused a significant increase in IGF-1 and IGF-1/IGFBP-3, an insignificant decrease in IGFBP-3, as compared to the control+placebo group. However, after six weeks of aerobic training and DOX treatment with $10mg{\cdot}kg^{-1}$ and or/ $20mg{\cdot}kg^{-1}$ an insignificant decrease in IGF-1, an insignificant increase in IGFBP-3 and a significant decrease in IGF-1/IGFBP-3 were detected, in comparison to $C+DOX_{10}$ and $C+DOX_{20}$. Conclusions: Hepatotoxicity of doxorubicin is dose-dependent and pretreatment with regular aerobic training may improve DOX-induced hepatotoxicity by up-regulation of IGFBP3.

• The Korea Journal of Herbology
• /
• v.26 no.4
• /
• pp.133-137
• /
• 2011

Objectives : Socheongryong-Tang (小靑龍湯, SCRT) has been widely used to treat respiratory disease. In this study, we investigated the protective effects of SCRT on hydrogen peroxide-induced hepatotoxicity. Methods : In the mouse primary liver cells, SCRT was pretreated for 1 h, and 1 mM $H_2O_2$ was treated to mouse primary liver cells. Cell viability was analyzed by using 3- 4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay. Also, the activity of AST, ALT and LDH were measured for the evaluation the protective effect of SCRT on $H_2O_2$-induced hepatotoxicity. Intracellular ROS level was analyzed by FACS. Results : SCRT pretreatment decreased $H_2O_2$-induced hepatotoxicity and intracellular ROS production. Pretreatment of SCRT significantly reduced the cytotoxic effect induced by $H_2O_2$, associated with reducing DNA fragmentation and AST, ALT, LDH activities. Conclusions : These results suggest that SCRT has protective effect against $H_2O_2$-induced hepatotoxicity.

• Archives of Pharmacal Research
• /
• v.27 no.7
• /
• pp.781-789
• /
• 2004

The effect of 1,8-cineole on cytochrome P450 (CYP) expression was investigated in male Sprague Dawley rats and female BALB/c mice. When rats were treated orally with 200, 400 and 800 mg/kg of 1,8-cineole for 3 consecutive days, the liver microsomal activities of benzy-loxyresorufin- and pentoxyresorufin-D-dealkylases and erythromycin N-demethylase were dose-dependently induced. The Western immunoblotting analyses clearly indicated the induction of CYP 2B1/2 and CYP 3A1/2 proteins by 1,8-cineole. At the doses employed, 1,8-cineole did not cause toxicity, including hepatotoxicity. Subsequently, 1,8-cineole was applied to study the role of metabolic activation in thioacetamide-induced hepatotoxicity and/or immunotoxicity in animal models. To investigate a possible role of metabolic activation by CYP enzymes in thioacetamide-induced hepatotoxicity, rats were pre-treated with 800 mg/kg of 1,8-cineole for 3 days, followed by a single intraperitoneal treatment with 50 and 100 mg/kg of thioacetamide in saline. 24 h later, thioacetamide-induced hepatotoxicity was significantly potentiated by the pretreatment with 1,8-cineole. When female BALB/c mice were pretreated with 800 mg/kg of 1,8-cineole for 3 days, followed by a single intraperitoneal treatment with 100 mg/kg of thioace-tamide, the antibody response to sheep red blood cells was significantly potentiated. In addition, the liver microsomal activities of CYP 2B enzymes were significantly induced by 1,8-cineole as in rats. Taken together, our results indicated that 1,8-cineole might be a useful CYP modulator in investigating the possible role of metabolic activation in chemical-induced hepato-toxicity and immunotoxicity.

• Journal of Pharmacopuncture
• /
• v.21 no.4
• /
• pp.249-257
• /
• 2018

Objectives: The hepatotoxicity induced by Acetaminophen (AAP) mostly mediated by effect on oxidative stress parameters. The Zataria multiflora (Z.M) is an herbal medicine with well-known antioxidant effect. The aim of this study is investigation of preventive effects of Z.M and Carvacrol (CAR) on AAP-induced hepatotoxicity in rats. Methods: Rats were randomly divided into four groups including: 1) Control, 2) Acetaminophen (AAP), 3) and 4) CAR. The saline, Z.M (200 mg/kg) and CAR (20 mg/kg) were administrated orally for 6 days, after that AAP (600 mg/kg) was administrated in the $7^{th}$ day. Blood sampling was performed on the first and last days. Also, the liver tissue was removed for evaluation of Malondyaldehide (MDA), Thiol content, Superoxide dismutase (SOD) and Catalase (CAT). Total Protein (tPro), Glutamic Oxaloacetic Transaminase (GOT), Glutamic Pyruvic Transaminase (GPT) and Alkaline Phosphatase (ALP) in liver tissue were evaluated. The changes (${\Delta}$) of enzymes activities were presented. Results: The ${\Delta}GOT$, ${\Delta}GPT$ and ${\Delta}ALP$ in CAR group significantly decreased compared to AAP group (P < 0.01 to P < 0.001) and ${\Delta}GPT$ in Z.M group was significantly reduced in comparison with AAP group (P < 0.05). Also, MDA, Thiol, SOD and CAT levels in treated groups were attenuated compared to AAP group (P < 0.05 to P < 0.001). Conclusion: Z.M and CAR have a powerful hepatoprotective effect. CAR is more effective than Z.M. Based on the results. Z.M and CAR could be potent supplementary agents against hepatotoxicity of AAP in patients.

• Proceedings of the Korea Environmental Mutagen Society Conference
• /
• 2002.11a
• /
• pp.43-50
• /
• 2002

• Proceedings of the Korean Society of Veterinary Clinics Conference
• /
• 2009.10a
• /
• pp.252-252
• /
• 2009

• Journal of Preventive Medicine and Public Health
• /
• v.33 no.1
• /
• pp.117-124
• /
• 2000

Objectives : It is the objective of this study to compare hepatotoxicity of nickel chloride and cadmium chloride with each other through IPRL(Isolated Perfused Rat Liver) method. Methods : Biochemical indicator of hepatic function such as AST(aspartate aminotransferase), ALT(alanine aminotransferase), LDH(lactate dehydrogenase) and perfusion flow rate were used as the indicator of hepatotoxicity. Oxygen consumption rate were used as vability indicator. $300({\pm}50)g$ - weighted rats were allocated randomly to each group($0{\mu}M,\;50{\mu}M,\;200{\mu}M\;NiCl_2\;and\;CdCl_2$ exposure) by 5, totally 25. After Krebs-Ringer bicarbonate butler solution flowed into the penal vein and passed the liver cell, it flowed out of vena cava. Liver was administered with each $NiCl_2\;and\;CdCl_2$ of each concentration and observed with buffer solution sampling time. Butler which got out of liver was sampled and then biochemical indicator of hepatotoxicity was measured. Results : AST, ALT, and LDH in buffer increased with sampling time much more in $CdCl_2$ exposure group than $NiCl_2$ exposure group in both 50 and $200{\mu}M$ and statistical significance w3s verified with 2-way repeated ANOVA. Viability was decreased more and more in all substances during passed time. Conclusions : It is inferred that $CdCl_2$ has stronger hepatotoxicity than $NiCl_2$. IPRL method would be used widely for acute hepatotoxicity when considerating the benefit of it.

• Biomolecules & Therapeutics
• /
• v.25 no.2
• /
• pp.112-121
• /
• 2017

Drug-induced liver injury (DILI) is the serious and fatal drug-associated adverse effect, but its incidence is very low and individual variation in severity is substantial. Acetaminophen (APAP)-induced liver injury accounts for >50% of reported DILI cases but little is known for the cause of individual variations in the severity. Intrinsic genetic variation is considered a key element but the identity of the genes was not well-established. Here, pre-biopsy method and microarray technique was applied to uncover the key genes for APAP-induced liver injury in mice, and a cause and effect experiment employing quantitative real-time PCR was conducted to confirm the correlation between the uncovered genes and APAP-induced hepatotoxicity. We identified the innately and differentially expressed genes of mice susceptible to APAP-induced hepatotoxicity in the pre-biopsied liver tissue before APAP treatment through microarray analysis of the global gene expression profiles (Affymetrix $GeneChip^{(R)}$ Mouse Gene 1.0 ST for 28,853 genes). Expression of 16 genes including Gdap10, Lpl, Gabra3 and Ccrn4l were significantly different (t-test: FDR <10%) more than 1.5 fold in the susceptible animals than resistant. To confirm the association with the susceptibility to APAP-induced hepatotoxicity, another set of animals were measured for the expression level of selected 4 genes (higher two and lower two genes) in the liver pre-biopsy and their sensitivity to APAP-induced hepatotoxicity was evaluated by post hoc. Notably, the expressions of Gabra3 and Lpl were significantly correlated with the severity of liver injury (p<0.05) demonstrating that these genes may be linked to the susceptibility to APAP-induced hepatotoxicity.