Dietary Fish Oil Aggravates Paracetamol-Induced Liver Injury in Mice

Abstract

Background: Paracetamol (APAP) hepatotoxicity remains the leading cause of drug-induced liver failure. Fish oil, which contains ω-3 fatty acids, has demonstrated therapeutic efficacy in several models of liver disease. Evidence for its use in APAP intoxication, however, is conflicting. The effects of fish oil supplementation on APAP-induced liver failure were investigated. Methods: Ten C57BL6/J mice were fed a diet based on menhaden fish oil (MEN) or soybean oil (SOY) for 3 weeks followed by APAP intoxication. In a second experiment, the prefeeding period was reduced to 5 days. In a third experiment, 10 mice received the study diets for 3 weeks, after which they received chronic, low-dose APAP administration for another 4 weeks. Finally, 10 mice received oral parenteral nutrition supplemented with either intravenous (IV) soybean-based or fish oil–based lipid emulsion for 19 days, followed by APAP intoxication. Results: The extent of hepatocellular necrosis (3.8 ± 0.2 vs 2.8 ± 0.2; P = .021) and serum alanine aminotransferase values (2807 ± 785 vs 554 ± 141 IU/L; P = .048) were significantly elevated in mice fed a MEN diet compared with SOY-diet fed controls. Long-term, low-dose APAP administration did not lead to liver injury irrespective of study diet. Pretreatment with soybean- or fish oil–based IV lipid emulsions followed by APAP intoxication demonstrated no significant differences in hepatic injury between groups. Conclusion: Within therapeutic ranges, APAP is harmless to the liver irrespective of dietary fat composition. IV use of fish oil did not increase APAP-induced hepatotoxicity, but animals fed a fish oil–based diet were more susceptible, rather than resistant, to APAP-induced hepatotoxicity.