• Title, Summary, Keyword: hepatotoxicity

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Reviews on the Hepatotoxicity of Tyrosine Kinase Inhibitors (티로신 키나아제 저해제의 간독성에 대한 고찰)

  • Han, Ji Min;Gwak, Hye Sun
    • Korean Journal of Clinical Pharmacy
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    • v.29 no.4
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    • pp.223-230
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    • 2019
  • Background: Small-molecule tyrosine kinase inhibitors (TKIs) have had major impacts on anticancer therapy by targeting the catalytic activities of dysregulated tyrosine kinases. TKIs have not presented traditional toxicities; however, some serious adverse effects, including hepatotoxicity, have been documented in clinical trials and post-marketing surveillance. Although TKI-induced hepatotoxicity can cause severe clinical complications in patients, the underlying mechanism is still unclear. Methods: Studies on TKI-induced hepatotoxicity were identified by Pubmed search, and relevant articles were reviewed. Results: Immunoallergic reaction, cytochrome P (CYP) 450 polymorphisms, and formation of reactive metabolites are under consideration as mechanisms of TKI-induced hepatotoxicity. Host protein-drug metabolite conjugates are recognized as antigens by class II major histocompatibility complexes and are believed to cause liver injuries. Polymorphisms in CYP, which influences TKI metabolism, can slow TKI metabolism and may induce development of hepatotoxicity. The formation of reactive metabolites during drug metabolism can induce hepatotoxicity by directly causing cytotoxicity, leading to cell dysfunction, and indirect toxicity by mediating secondary immune reactions. Concurrent use of various medications with TKI can also cause hepatotoxicity by affecting drug transporter or enzyme activities. Conclusion: Periodic monitoring of patients taking TKIs and risk/benefit reassessments though post marketing surveillance are necessary to prevent hepatotoxicity.

Correlation between Protein Methylation and Hepatotoxicity (단백질메칠화 반응과 간독성간의 상관관계)

  • 김재현;박창원;이주한;백윤기;문화회;홍성렬;이향우
    • Biomolecules & Therapeutics
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    • v.2 no.1
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    • pp.47-53
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    • 1994
  • The methylation response as well as the level of methyl donor substance, 5-adenosyl-L-methionine (SAM) has been suggested to be related to hepatotoxicity including hepatocarcinogenesis. But direct correlation between protein methylation and hepatotoxicity has not been established to the present. To observe relationship between protein methylation and short-term hepatotoxicity induced by chemical substances, the activities of protein methylase I and II (PM I, PM II) were examined in cytosolic fraction of SD rat treated orally with acetaminophen(AA), $\alpha$-naphtyl-isothiocyanate (ANIT) and tetracycline (TC) that was known to produce necrosis, cholestasis and steatosis respectively. To evaluate the degree of hepatotoxicity induced by each chemicals, we observed the serum levels of indicative parameters and histopathological alteration. In AA treated group, the activities of PM I were increased at 6, 12 hours after administration, prior to the appearance of the hepatotoxicity by clinical parameters. It was suggested that the levels of PM I were related with the initial stage of hepatotoxic mechanism induced by AA. In ANIT treated group, though most of clinical parameters were significantly increased at 24, 48 hours after administration, the activity of PM I was not changed, indicating that ANIT induced hepatotoxicity was not coupled to protein methylation.

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Protective Effects of Iljungbogan-Tang on Acute Hepatotoxicity Induced by $CCL_4$ and Acetaminophen (급성 간독성에 대한 일중보간탕(一中補肝湯)의 해독 효과에 관한 연구)

  • Kim, Joon-Myoung;Park, Yang-Chun;Son, Gi-Jung
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.20 no.2
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    • pp.410-413
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    • 2006
  • This study was done to investigate the protective effects of Iljungbogan-Tang on acute hepatotoxicity of rats induced by $CCL_4$ and acetaminophen. The subject animals were divided into 3 groups : control group(administrated 0.5% carboxymethyl cellulose), sample group(30, 100, 300, 600mg/kg administrated), positive control group (administrated silymarine), Acute hepatotoxicity of rats were induced by $CCL_4$ and acetaminophen, and the serum transaminase(AST, ALT) were measured for enzyme activities. The inhibitory effects on the serum AST activities were noted in sample group(100, 300, 600mg/kg administrated) on hepatotoxicity of rats induced by $CCL_4$. The inhibitory effects on the serum AST, ALT activities were noted in sample group(30mg/kg administrated) on hepatotoxicity of rats induced by acetaminophen. The inhibitory effects on the serum AST activities were noted in sample group(600mg/kg single dose administrated) on hepatotoxicity of rats induced by acetaminophen. It is considered that Iljungbogan-Tang has protective effects against hepatotoxicity in rats induced by $CCL_4$ and acetaminophen. So it is required to study about the actions of mutual relation of medicines and patho-mechanism through experiment.

Effects of N-Acetyl Cysteine and Silymarin on 1-Bromopropane-induced Hepatotoxicity in Mice (1-Bromopropane의 간독성에 미치는 N-Acetyl Cysteine과 Silymarin의 영향)

  • Lee, Sang-Kyu;Kang, Mi-Jeong;Jeon, Tae-Won;Jeong, Tae-Cheon
    • YAKHAK HOEJI
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    • v.54 no.2
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    • pp.97-101
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    • 2010
  • Recently, it was found that the formation of reactive metabolites by cytochrome P450s as well as the depletion of glutathione would play important roles in hepatotoxicity induced by 1-bromopropane. In the present study, possible roles of anti-oxidants in 1-bromopropane-induced hepatotoxicity were investigated in male ICR mice. The hepatotoxicity induced by 1-bromopropane was significantly protected by the co-treatment with either N-acetyl cysteine or silymarin. 1-Bromopropane-induced decrease in hepatic glutathione level was significantly protected by the pretreatment with N-acetyl cysteine. Taken together, the present results indicated that the reduction of hepatic glutathione level caused by 1-bromopropane treatment might be associated in 1-bromopropane-induced hepatotoxicity in mice.

Inducible Mechanisms for Hepatotoxicity caused by Traditional Korean Medicines in a View of Toxicology (독성학적 측면에서의 한약에 의한 간독성 유발과 기전)

  • Park, Yeong-Chul;Park, Hae-Mo;Lee, Sun-Dong
    • The Journal of Korean Medicine
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    • v.32 no.4
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    • pp.48-67
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    • 2011
  • Objectives: There has been a lot of controversy about whether Korean traditional medicines cause drug-induced hepatotoxicity or not. However, this controversy has not been examined from a scientific approach, especially in terms of toxicology. Thus, this article for traditional Korean medicine-induced hepatotoxicity was reviewed on a basis of toxicological assessment. Methods: Toxicological assessments were carried out in a view of reactive intermediates formation from biotransformation in animals based on cytochrome P450 activity inducing oxidative stress, and case reports in world-wide. Results and Conclusions: Several herbal materials used for traditional Korean medicines were identified as possible agents causing drug-induced hepatotoxicity. Most of these agents seem to produce toxic reactive intermediates caused by cytochrome P450. Oxidative stress followed by cytochrome P450 activation could also be a reason for herb-induced hepatotoxicity. Plausible prevention of herb-induced hepatotoxicity was suggested.

Prediction of the Hepatotoxicity Risk Factor Induced by Antituberculosis Agents in Koreans (한국인의 항결핵제에 의한 간독성 위험인자 예측)

  • Lee, Ji-Sun;Kim, Hyun-Ah;Cho, Eun;Lee, Ok-Sang;Lim, Sung-Cil
    • YAKHAK HOEJI
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    • v.55 no.4
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    • pp.352-360
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    • 2011
  • Standard combination chemotherapy including isoniazid, rifampin, pyrazinamide, and ethambutol is very effective against tuberculosis. But, these medicines can cause hepatotoxicity which is the main reason for treatment interruption or change in drug regimen. In order to identify risk factors associated with hepatotoxcity in Koreans and assess elevated baseline LFTs' contributions to hepatotoxicity, a retrospective case control study was performed. The medical records of 277 patients who diagnosed with tuberculosis at a community hospital from January 1st, 2007 to June 30th, 2010 were reviewed. Patients were categorized into 3 groups (non toxic group, patients without increase in LFT levels; mild to moderate hepatotoxic group and severe hepatotoxic group). And the correlation between risk factors and hepatotoxicity was analyzed by using SPSS program. The overall incidence of hepatotoxicity was 18% and 8.7% of patients developed severe toxicity. Patients in the severe toxic group had the longest treatment period among the three groups. In 75% of severe toxic group, hepatotoxicity occurred within 18.3 days after starting medication. Hypoalbuminemia (serum albumin <3 g/dl) was a significant risk factor for development of severe toxicity. Elevated baseline transaminase (except ALT), total bilirubin, and preexisting hepatitis were also risk factors which were more than twice as likely to increase risk of severe hepatotoxicity (p>0.05). In conclusion, hypoalbuminemia (serum albumin level <3 g/dl) was a significant risk factor for anti-tuberculosis druginduced severe toxicity. Therefore, before starting antituberculosis chemotherapy, serum albumin level should be assessed at baseline. In high-risk patients (hypoalbuminemia, elevated LFTs) for hepatotoxicty, liver function should be closely monitored up to at least 21 days after taking medication.

Effects of Glycyrrhizae Radix on Acetaminophen-induced Hepatotoxicity in Mice

  • Aree Moon;Lee, Mi-Kyung;Kim, Chang-Ok
    • Biomolecules & Therapeutics
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    • v.3 no.3
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    • pp.229-232
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    • 1995
  • In order to study if Glycyrrhizae Radix (GR) has protective effects on hepatotoxicity of acetaminophen in mouse, one of the species which are sensitive to acetaminophen-induced hepatotoxicity, effects of GR on liver weight to body weight ratio, serum alanine and aspartate transaminase (ALT and AST) activities, hepatic UDP-GT2 activity, and histopathologic changes were determined in acetaminophen-treated mice. Liver weight to body weight ratio and UDP-GT2 activity in mouse liver were not altered by GR. However, GR pretreatment lowered serum ALT and AST activities by 77% and 90% respectively, and diminished the degree of centrilobular necrosis caused by acetaminophen in liver as determined by histopathologic observation. These results suggest a possible protective effect of GR against the acetaminophen-induced hepatotoxicity in mice.

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Hepatoprotective and Antioxidative Effects of Alisma orientale

  • Rhew, Kwang-Yul;Choi, Hyuck-Jai;Kim, Nam-Jae;Lee, Jang-Hoon
    • Natural Product Sciences
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    • v.17 no.4
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    • pp.285-290
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    • 2011
  • The rhizome of Alisma orientale Juzep (Alismataceae) has been used as a crude drug for diabetes, edema, inflammation and urinary disturbances in oriental medicine. Recent animal studies have shown that the extract of Alisma orientale rhizome (AOR) can potently lower high levels of serum lipids and improve insulin resistance, which are usually detected in patients and animals with non-alcoholic fatty liver disease. So, we studied the antioxidative effects of AOR extracts and fraction in vitro and their protective effects against acute hepatotoxicity induced by $CCl_4$ in vivo.. We then investigated the effects of each fraction on hepatotoxicity induced by tert-butyl hydroperoxide (t-BHP). DAOR (dichloromethane fraction of the Alisma orientale rhizome) scavenged free radicals and superoxide anions. DAOR protected against $CCl_4$ induced hepatotoxicity. DAOR had hepatoprotective and antioxidative effects against t-BHP-induced hepatotoxicity in HepG2 cells and in rats.

RECENT ADVANCES IN HEPATOTOXICITY STUDIES

  • Satoh, Tetsuo
    • Toxicological Research
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    • v.7 no.2
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    • pp.113-128
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    • 1991
  • Hepatotoxicity has many facets. Those to be discussed in this review include the mechanism for the hepatotoxic effects, nature of the injury, and animal models of hepatotoxicity suitable for the detection of chemical injury. Some therapeutic drugs used for treatment of hepatitis are also presented. In addition, as an important and serious problem in future, alternative toxicity testing is discussed.

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Biphasic Effects of Nitric Oxide in Liver Toxicity (간장독성에서 니트릭 옥시드의 양면적 효과)

  • Park, Chang-Won;Cho, Dae-Hyun;Hong, Sung-Youl;Han, Jeung-Whan;Lee, Hyang-Woo
    • 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.

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