title: The PPAR activator docosahexaenoic acid prevents acetaminophen hepatotoxicity in male CD-1 mice.
abstract: Acetaminophen (APAP)-induced hepatocellular necrosis can be prevented by treatment with peroxisome proliferators. This protection is associated with lowered protein arylation and glutathione depletion in mice. Peroxisome proliferators have been shown to activate nuclear receptors. These receptors, termed peroxisome proliferator activated receptors (PPARs), can also be activated by free fatty acids. This study was designed to determine if treatment with the PPAR activator docosahexaenoic acid (DHA) would also lower APAP toxicity. Male CD-1 mice received 250 mg DHA/kg or 500 mg clofibrate (CFB)/kg, i.p., for 5 d. Controls received corn oil vehicle, i.p. After overnight fasting, mice received 800 mg APAP/kg, p.o. At 24 h after APAP, hepatotoxicity was evident in control mice by elevated plasma sorbitol dehydrogenase activity (SDH) and histologic evidence of hepatic degeneration and necrosis. As expected, CFB pretreatment significantly decreased this. Similarly, DHA protected against APAP-induced hepatotoxicity at 24 h after challenge. However, treatment with DHA did not increase hepatic glutathione prior to APAP, as previously shown with CFB. Interestingly, DHA did not increase palmitoyl coenzyme A (CoA) oxidase activity or other biochemical parameters associated with peroxisome proliferation after 5 d of treatment at 250 mg/kg. No significant alterations in microsomal APAP glucuronidation or cytochrome P-450-mediated bioactivation were detected either. Collectively, these results show that DHA also prevents APAP-induced hepatotoxicity at 24 h after challenge. However, the association between resistance against APAP-induced liver injury, PPAR activation, and peroxisome proliferation is not clearly understood.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Nguyen
authors.forename: J M
authors.initials: JM
authors.lastname: Carbone
authors.forename: V M
authors.initials: VM
authors.lastname: Silva
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: G E
authors.initials: GE
authors.lastname: Hennig
authors.forename: H E
authors.initials: HE
authors.lastname: Whiteley
authors.forename: J E
authors.initials: JE
authors.lastname: Manautou
mesh_terms: D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002994:Clofibrate / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005965:Glucuronates / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D000924:Anticholesteremic Agents; D005965:Glucuronates; D018160:Receptors, Cytoplasmic and Nuclear; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; D010171:Palmitoyl Coenzyme A; D004281:Docosahexaenoic Acids; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D013385:Succinate Dehydrogenase; D002994:Clofibrate