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Protective effect of chlormethiazole, a sedative, against acetaminophen-induced liver injury in mice.

Title
Protective effect of chlormethiazole, a sedative, against acetaminophen-induced liver injury in mice.
Authors
Lee H.C.Jung S.A.Jung H.K.Yi S.Y.Kim D.Y.Moon I.H.Park S.S.
Ewha Authors
문일환이선영정성애정혜경
SCOPUS Author ID
문일환scopus; 이선영scopus; 정성애scopus; 정혜경scopus
Issue Date
1999
Journal Title
The Korean journal of internal medicine
ISSN
1226-3303JCR Link
Citation
The Korean journal of internal medicine vol. 14, no. 2, pp. 27 - 33
Indexed
SCIE; SCOPUS; KCI scopus
Document Type
Article
Abstract
OBJECTIVES: The hepatotoxicity of acetaminophen is not a result of the parent compound but is mediated by its reactive metabolite N-acetyl-p-benzoquinone imine. Cytochrome P4502E1 (CYP2E1) is the principal enzyme of this biotransformation, which accounts for approximately 52% of the bioactivation in human microsomes. Recently, chlormethiazole a sedative drug, is reported to be an efficient inhibitor of CYP2E1 activity in human beings. In this study we wished to evaluate whether chlormethiazole, an inhibitor of CYP2E1, could prevent acetaminophen-induced liver injury in mice. METHODS: Acetaminophen, at doses ranging from 200 to 600 mg/kg, was injected into the peritoneum of female C57BL/6 inbred mice fasted for four hours. Chlormethiazole (60 mg/kg) or 5% dextrose water was given 30 min before or 2 h after acetaminophen. Serum aminotransferase activities, histologic index score, survival rate and hepatic malondialdehyde levels were compared. RESULTS: Pretreatment with chlormethiazole 30 min before 400 mg/kg of acetaminophen completely inhibited acetaminophen-induced liver injury (median 118.5 U/L, range 75 to 142 vs. 14,070 U/L, range 5980 to 27,680 for AST; 49 U/L, range 41 to 64 vs. 15,330 U/L, range 13,920 to 15,940 for ALT). In mice receiving chlormethiazole 2 h after acetaminophen, the mean AST and ALT levels were also less elevated, reaching only 20% of the value of acetaminophen-only group. These protective effects were confirmed histologically. Whereas more than 50% of mice died at 500 mg/kg of acetaminophen, all the mice pretreated with chlormethiazole survived at the same dose. CONCLUSION: Chlormethiazole effectively reduces acetaminophen-induced liver injury in mice. Further studies are needed to assess its role in humans.
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의과대학 > 의학과 > Journal papers
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