TProtective effect of chlormethiazole, a sedative, against acetaminophen-induced liver injury in mice.
- Author:
Han Chu LEE
1
;
Sung Ae JUNG
;
Hye Kyung JUNG
;
Sun Young YI
;
Doe Young KIM
;
Il Hwan MOON
;
Sung Su PARK
Author Information
1. Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea.
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Chlormethiazole;
Acetaminophen;
Liver injury
- MeSH:
Acetaminophen/toxicity*;
Acetaminophen/metabolism;
Acetaminophen/antagonists & inhibitors;
Analgesics, Non-Narcotic/toxicity*;
Analgesics, Non-Narcotic/metabolism;
Analgesics, Non-Narcotic/antagonists & inhibitors;
Animal;
Chlormethiazole/pharmacology*;
Cytochrome P-450 CYP2E1/antagonists & inhibitors;
Enzyme Inhibitors/pharmacology;
Female;
Human;
Liver/metabolism;
Liver/injuries*;
Liver/drug effects*;
Mice;
Mice, Inbred C57BL;
Sedatives, Nonbarbiturate/pharmacology*;
Support, Non-U.S. Gov't
- From:The Korean Journal of Internal Medicine
1999;14(2):27-33
- CountryRepublic of Korea
- Language:English
-
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.
