• 약학회지
• /
• 제59권5호
• /
• pp.201-206
• /
• 2015

The aim of the present study was to optimize in vitro method for the prediction of drug-induced liver injury using human liver microsomes (HLM). Cytotoxicity test of cyclophosphamide and acetaminophen in HepG2 cells cultured with HLM showed that the newly established condition using 0.375 mg/ml HLM for 24 hr incubation was comparable or more sensitive than the previously established condition using 0.75 mg/ml HLM for 12 hr incubation. Although the cytotoxic effect of troglitazone was completely attenuated by 0.75 mg/ml HLM, it was augmented by 0.375 mg/ml HLM in the presence of the NADPH-generating system. The cytotoxic effect of chlormezanone, a withdrawn drug due to hepatotoxicity in human, was increased by HLM in the presence of the NADPH-generating system. In contrast, the cytotoxic effect of methapyrilene, a withdrawn drug due to hepatotoxicity in rats, was decreased by HLM in the presence of the NADPH-generating system. The present study suggests that the optimized in vitro method using HLM can be useful for the prediction of drug-induced hepatotoxicity.

• Toxicological Research
• /
• 제11권2호
• /
• pp.181-185
• /
• 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.

• 대한한방내과학회지
• /
• 제40권2호
• /
• pp.201-207
• /
• 2019

Objectives: The purpose of this case study is to report the effect of Korean Medicine treatment on a patient diagnosed with drug-induced liver injury by oral administration of acetaminophen. Methods: A 21-year-old male patient with drug-induced liver injury visited the clinic five times from January 28th, 2019 to March 16th, 2019. The patient took Saenggan-tang extract during the treatment period. Results: The levels of serum alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) were significantly decreased. The chief complaints of the patient, such as yellow-red urine and fatigue, were also relieved. Conclusion: Traditional Korean medicine has a beneficial effect on drug-induced liver injury.

• 대한한의학방제학회지
• /
• 제11권1호
• /
• pp.129-149
• /
• 2003

Liver is an important target of the toxicity of drugs, xenobiotics and oxidative stress. Acetaminophen pverdose causes acute liver injury in both humans and animals. This study was performed to observe the effect of sachunwhan and its component groups on recovery of hepatoxicity in acetaminophen treated rats. The experimental group was divided into 4 groups: sachungwhan(SC), samultang group(SC-1: 當歸, 川芎), chungyul group(SC-2: 龍膽草, 大黃, 梔子), and haepyo group(SC-3:羌活, 防風). Under the same condition Normal group was fed basal diet and water; Control group was injected acetaminophen and fed basal diet for 2 weeks; Experimental groups were injected acetaminophen and fed each extracts for 2 weeks respectively. The results were obtained as follows: 1. In the study on antioxidative defense system in vivo, SC reduced the amount of lipid peroxide in both serum and liver and showed activity on antioxidative enzymes such as catalase, glutathion. Other groups had effect only on glutathion. 2. In the study on hepatotoxicity(GOT, GPT, ${\gamma}$-GTP, ALP, LDH, Bilirubin), SC had a significant effect on recovery of hepatoxicity in acetaminophen treated rats. Other groups had no effect except SC-1 having effect on ${\gamma}$-GTP. As results shown, only Sachungwhan(SC) has significant effects on recovery of hepatoxicity and antioxidative defense system in vivo. These results suggest that Sachungwhan(SC) made antioxidative defense system active and it seemed to be very important to its effect on recovery of hepatoxicity. In the other hand, Component groups had no effect on recoverv of hepatoxicity and antioxidative defense system in vivo. This was thought that component drugs' cooperative synergy effect would be important to Sachungwhan(SC)'s effects mentioned in this paper.

• 대한한의학방제학회지
• /
• 제13권1호
• /
• pp.9-33
• /
• 2005

Acetaminophen, which causes acute liver min in humans and animals, has made useful inducer of hepatoxicity for studying hepatopreventive drugs. Injinhotang is known as one of the hepatopreventive drugs. However, its mechanism of recovery of hepatoxicity treated with acetaminophen is poorly understood. this study was performed to observe the antioxidative effect of injinhotang extract and its several combination groups. The results were obtained as follows:1. In the study on free radical scavenging effect in vitro(the suppressing effect on peroxidation of linoleic acid on concentration, the scavenging effect of DPPH radical, inhibitory effect of superoxide in xanthine-xanthine oxidase system and the inhibitory effect on lipid peroxidation reaction by hydroxy radical in H2O2-Fe2+system, injinhotang have more effect than its components groups relatively. 2. In the study on antioxidants system in vivo(the level of serum LPO, the level of hepatic LPO, catalase, GSH, GST), only injnhotang has a significant effect. 3. In the study on hepatotoxicity(GOT, GPT, $\gamma$-GTP, ALP, LDH, b ilirubin), only injinhotang has a significant effect. These results suggest that injinhotang has the protective effect on acetaminophen-induced hepatoxicity. The mechanisms of these are supposed to be involved in antioxidant and three drugs' cooperative synergy effect.

• 동의생리병리학회지
• /
• 제27권5호
• /
• pp.617-624
• /
• 2013

The purpose of this study is to investigate the protective effects of 25 herbal formulas on acetaminophen (APAP) or D-galactosamine (D-GalN)-induced hepatotoxicity in primary rat hepatocytes. Cell viability was measured using by Cell Counting Kit-8. 15 kinds of herbal formulas significantly reversed the cell viabilities of D-GalN-treated rat hepatocytes compared with D-GalN alone (p<0.05). In particular, 9 herbal formulas (Bangpungtongseong-san, Bojungikgi-tang, Galgeun-tang, Gumiganghwal-tang, Guibi-tang, Sagunja-tang, Samsoeum, Pyeongwi-san and Yijin-tang) showed the potent protective effects. However, 8 herbal formula exerted weak protective effects and 2 herbal formula did not exert effects on hepatotoxicity by D-GalN. On APAP-induced hepatotoxicity, 7 kinds of herbal formulas increased the viabilities of hepatocytes compare with APAP alone (p<0.05). These results could be provide a valuable information for the future in vivo or clinical studies to predict the hepatoprotective effects of herbal formulas.

• Biomolecules & Therapeutics
• /
• 제5권2호
• /
• pp.194-201
• /
• 1997

The hepatoprotective activity of six extracts (BE, EE, HH, PS-1, PS-2, KP) from Artimisia iwayomogi was investigated against experimentally produced hepatic damages. Silymarin, DDB and UDCA were used as reference compounds. Treatment with PS-1 extract reduced hepatic demages induced by $CCl_4$, acetaminophen and ANIT but it did not alter ethionine-induced hepatotoxicity In addition, PS-1 extract showed a protective effect against chronic $CCl_4$-induced hepatotoxicity as well as liver regeneration. PS-2 and KP extracts exhibited significant antihepatotoxic effects on D-galactosamine-induced hepatitis. Treatment with EE extract inhibited ethionine-induced fatty liver. These data indicate that the PS-1 extract is the roost hepato-protective constituent and rationalize the traditional use of this plant in hepatobiliary disorders.

• 한국독성학회:학술대회논문집
• /
• 한국독성학회 1998년도 국제심포지움 및 추계학술대회
• /
• pp.56-56
• /
• 1998

• Biomolecules & Therapeutics
• /
• 제17권4호
• /
• pp.438-445
• /
• 2009

We investigated global gene expression from both mouse liver and mouse hepatic cell lines treated with acetaminophen (APAP) in order to compare in vivo and in vitro profiles and to assess the feasibility of the two systems. During our analyses of gene expression profiles, we picked up several down-regulated genes, such as the cytochrome P450 family 51 (Cyp51), sulfotransferase family cytosolic 1C member 2 (Sult1c2), 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (Hmgcs1), and several genes that were up-regulated by APAP, such as growth arrest and DNA-damage-inducible 45 alpha (Gadd45a), transformation related protein 53 inducible nuclear protein 1 (Trp53inp1) and zinc finger protein 688 (Zfp688). For validation of gene function, synthesized short interfering RNAs (siRNAs) for these genes were transfected in a mouse hepatic cell line, BNL CL.2, for investigation of cell viability and mRNA expression level. We found that siRNA transfection of these genes induced down-regulation of respective mRNA expression and decreased cell viability. siRNA transfection for Cyp51 and others induced morphological alterations, such as membrane thickening and nuclear condensation. Taken together, siRNA transfection of these six genes decreased cell viability and induced alteration in cellular morphology, along with effective inhibition of respective mRNA, suggesting that these genes could be associated with APAP-induced toxicity. Furthermore, these genes may be used in the investigation of hepatotoxicity, for better understanding of its mechanism.

• Molecules and Cells
• /
• 제38권10호
• /
• pp.843-850
• /
• 2015

The1hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose.