Protection against acetaminophen hepatotoxicity by a single dose of clofibrate: effects on selective protein arylation and glutathione depletion.
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.
Manautou
J E
JE
Department of Pharmaceutical Sciences, University of Connecticut, Storrs 06269-2092, USA.
Emeigh Hart
S G
SG
Khairallah
E A
EA
Cohen
S D
SD
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002994:Clofibrate / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D003314:Corn Oil / Q000008:administration & dosage; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D011506:Proteins / Q000378:metabolism; D013194:Staining and Labeling; D013438:Sulfhydryl Compounds / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D000960:Hypolipidemic Agents; D011506:Proteins; D013438:Sulfhydryl Compounds; D000082:Acetaminophen; D003314:Corn Oil; D007064:L-Iditol 2-Dehydrogenase; D005978:Glutathione; D002994:Clofibrate