Protective Effect of Chlormethiazole , a Sedative , against Acetaminophen - Induced Liver Injury in Mice

Lee, Han Chu; Jung, Sung Ae; Jung, Hye Kyung; Yi, Sun Young; Kim, Doe Young; Moon, Il Hwan; Park, Sung Su

doi:10.3904/kjim.1999.14.2.27

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…Chlormethiazole (CMZ), a drug used for alcohol withdrawal and agitation, and an efficient inhibitor of CYP2E1 activity, 26 was used to try to prevent the Jo2 agonist Fas antibody-induced liver injury found in Pyrtreated mice. Mice were divided into Sal (n ϭ 3), Pyr/Jo2 (n ϭ 6), and Pyr/Jo2 plus CMZ (n ϭ 16) groups, respectively.…”

Section: Methodsmentioning

confidence: 99%

Induction of cytochrome P450 2E1 increases hepatotoxicity caused by Fas agonistic Jo2 antibody in mice†

Wang

Cederbaum

2005

Hepatology

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Cytochrome P450 2E1 (CYP2E1) may be a central pathway in generating oxidative stress, reactive oxygen species, and causing hepatotoxic injury by alcohol and various hepatotoxins. This study evaluated the ability of CYP2E1 to potentiate or synergize the hepatotoxicity of Fas in vivo. C57BL/6 mice were injected intraperitoneally with pyrazole (Pyr) to induce CYP2E1. Then, 16-hour fasted mice were administered agonistic Jo2 anti-Fas antibody ip. Other mice were treated with Pyr or Jo2 alone. Levels of serum aminotransferase were 8.3-and 6.3-fold higher in the Pyr/Jo2 group compared with Jo2 alone, respectively. Histological evaluation of liver showed more extensive acidophilic necrosis and severe pathological changes in the Pyr/Jo2-treated mice. DNA fragmentation and caspase-8 and -3 activities were more elevated in the Pyr/Jo2 group compared with Jo2 alone. CYP2E1 activity and protein levels were higher in the Pyr/Jo2 group than in Jo2 alone. Levels of inducible nitric oxide synthase, 3-nitrotyrosine protein adducts, malondialdehyde, and protein carbonyls were also higher in the Pyr/Jo2 group compared with Jo2 alone. Glutathione and activities of catalase and Cu-Zn superoxide dismutase were decreased in the Pyr/Jo2 group. Administration of chlormethiazole, an inhibitor of CYP2E1, to the Pyr/Jo2-treated mice caused a significant decrease of alanine aminotransferase and liver pathological changes in association with a decrease in CYP2E1 protein and activity. In conclusion, enhanced hepatotoxicity of Fas was found in mice with elevated levels of CYP2E1. We speculate that overexpression of CYP2E1 might synergize and increase the susceptibility to Fas induced-liver injury.(HEPATOLOGY 2005;42:400-410.)

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Section: Methodsmentioning

confidence: 99%

Induction of cytochrome P450 2E1 increases hepatotoxicity caused by Fas agonistic Jo2 antibody in mice†

Wang

Cederbaum

2005

Hepatology

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“…They demonstrated that chlormethiazol was able to prevent liver injury in mice resulting in the survival of mice administered a high dose (500 mg/kg) of acetaminophen. A greater than 50 % death rate was observed in mice that were not co-administered chlormethiazol (Lee et al 1999). …”

Section: Introductionmentioning

confidence: 99%

Using random forest and decision tree models for a new vehicle prediction approach in computational toxicology

et al. 2015

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Drug vehicles are chemical carriers that provide beneficial aid to the drugs they bear. Taking advantage of their favourable properties can potentially allow the safer use of drugs that are considered highly toxic. A means for vehicle selection without experimental trial would therefore be of benefit in saving time and money for the industry. Although machine learning is increasingly used in predictive toxicology, to our knowledge there is no reported work in using machine learning techniques to model drug-vehicle relationships for vehicle selection to minimise toxicity. In this paper we demonstrate the use of data mining and machine learning techniques to process, extract and build models based on classifiers (decision trees and random forests) that allow us to predict which vehicle would be most suited to reduce a drug's toxicity. Using data acquired from the National Institute of Health's (NIH) Developmental Therapeutics Program (DTP) we propose a methodology using an area under a curve (AUC) approach that allows us to distinguish which vehicle provides the best toxicity profile for a drug and build classification models based on this knowledge. Our results show that we can achieve prediction accuracies of 80 % using random forest models whilst the decision tree models produce Communicated by D. Neagu. Electronic supplementary materialThe online version of this article (doi:10.1007/s00500-015-1925-9) contains supplementary material, which is available to authorized users.

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“…CMZ is thought to be a specific inhibitor of CYP2E1, 15 and it has been shown to ameliorate CYP2E1-mediated liver damage in rats treated chronically with ethanol, 16 in mice treated with acetaminophen 17 or mice treated with Jo2/pyrazole. 12 CYP2E1-knockout mice have been used in studies on toxicity of acetaminophen, 18 carbon tetrachloride, 19 chloroform, 20 and alcohol.…”

Section: Lps Directly Causes Liver Injury By Mechanisms Involving Infmentioning

confidence: 99%

Enhancement by pyrazole of lipopolysaccharide-induced liver injury in mice: Role of cytochrome P450 2E1 and 2A5

Cederbaum

2006

Hepatology

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The mechanisms by which alcohol causes liver injury are still not certain. Either LPS or CYP2E1 are considered independent risk factors involved in alcoholic liver disease, but mutual relationships or interactions between them are unknown. In the present study, the possible synergistic action of CYP2E1 and LPS in liver injury was investigated by evaluating the effects of pyrazole (inducer of CYP2E1), Chlormethiazole (CMZ), an inhibitor of CYP2E1, and CYP2E1-knockout mice. Mice were injected with pyrazole (150 mg/kg, ip) daily for 2 days, followed by LPS injection (4 mg/kg, ip). CMZ (50mg/kg, ip) was administered 15 h before and 30 min after LPS treatment, respectively. LPS-induced liver injury was enhanced by pyrazole, as indicated by pathological changes and increases in ALT and AST, and positive TUNEL staining. LPS-induced oxidative stress was also enhanced by pyrazole as indicated by increases in 4-hydroxy-2-nonenal and 3-nitrotyrosine adduct formation. CMZ protected against the pyrazole enhanced LPS liver injury and oxidative stress. CYP2E1 but also CYP2A5 were increased by the pyrazole/LPS treatment. CMZ decreased the elevated CYP2E1 activity by 90%, but CYP2A5 activity was also lowered (30%-50%). CYP2E1-knockout mice exhibited only minor liver injury after treatment with pyrazole/ LPS, but wild-type mice exhibited severe liver injury. While no CYP2E1 was present in the CYP2E1 knockout mice, CYP2A5 activity was also lower. In conclusion, induction of CYP2E1 plays an important role in the enhancement of LPS liver injury by pyrazole, but some contribution by CYP2A5 cannot be excluded. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/ suppmat/index.html). (HEPATOLOGY 2006;44:263-274.)

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Protective Effect of Chlormethiazole , a Sedative , against Acetaminophen - Induced Liver Injury in Mice

Cited by 4 publications

References 25 publications

Induction of cytochrome P450 2E1 increases hepatotoxicity caused by Fas agonistic Jo2 antibody in mice†

Induction of cytochrome P450 2E1 increases hepatotoxicity caused by Fas agonistic Jo2 antibody in mice†

Using random forest and decision tree models for a new vehicle prediction approach in computational toxicology

Enhancement by pyrazole of lipopolysaccharide-induced liver injury in mice: Role of cytochrome P450 2E1 and 2A5

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