Protection against acetaminophen hepatotoxicity by a single dose of clofibrate: Effects on selective protein arylation and glutathione depletion

被引:40
作者
Manautou, JE
Hart, SGE
Khairallah, EA
Cohen, SD
机构
[1] UNIV CONNECTICUT,SCH PHARM,DEPT PHARMACEUT SCI,TOXICOL PROGRAM,STORRS,CT 06269
[2] UNIV CONNECTICUT,DEPT MOLEC & CELL BIOL,STORRS,CT 06269
来源
FUNDAMENTAL AND APPLIED TOXICOLOGY | 1996年 / 29卷 / 02期
关键词
D O I
10.1006/faat.1996.0026
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Previous reports demonstrated that repeated administration of peroxisome proliferators protects against acetaminophen (APAP) hepatotoxicity in mice. This protection was associated with a decrease in APAP's selective protein arylation and glutathione depletion. This study was conducted to determine if a single dose of clofibrate (CFB), rather than repeated doses, would similarly prevent APAP toxicity. CD-1 male mice received a single dose of 500 mg CFB/kg and controls were given corn oil 24 hr prior to APAP challenge. After an 18-hr fast, mice were challenged with 800 mg APAP/kg (in 50% propylene glycol) and killed at 4 or 12 hr. Other mice similarly pretreated were killed without APAP challenge. The results showed that pretreatment with a single CFB dose significantly decreased APAP-induced hepatotoxicity. At 12 hr after APAP plasma sorbitol dehydrogenase activity and the severity of hepatocellular necrosis were decreased in CFB pretreated mice. Surprisingly, no differences in hepatic nonprotein sulfhydryl (NPSH) depletion or selective arylation of target proteins in cytosol were observed at 4 hr after APAP challenge. Neither did a single dose of CFB significantly alter hepatic NPSH content prior to APAP challenge. These results indicate that protection against APAP hepatotoxicity by CFB does not require repeated administration, and the absence of significant alterations in APAP's selective protein arylation or glutathione depletion suggests that the protection against APAP hepatotoxicity after a single treatment with CFB may differ mechanistically from the protection observed after repeated CFB dosing. (C) 1996 Society of Toxicology
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页码:229 / 237
页数:9
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