Hepatic metabolic alterations in rats treated with low-dose endotoxin and aspirin: an animal model of Reye's syndrome.
The administration of a sublethal dose of endotoxin (LPS) followed one hour later by a low dose of aspirin (LPS + ASA) to fasted rats leads to biochemical perturbations similar to Reye's syndrome. In this study hepatic energy metabolism was assessed in freeze-clamped liver samples (12 hours posttreatment) obtained from (250 to 300 g Sprague-Dawley) rats. The administration of aspirin alone to fasted rats did not significantly alter the hepatic levels of adenine nucleotides, total ketones, or acyl-CoA thioesters as compared to controls. In contrast, in both LPS and LPS + ASA samples, there were declines in ATP/ADP ratio (P less than .005), total ketones (P less than .001) and acetyl CoA (P less than .005) compared to their respective controls. A striking alteration in acyl-CoA thioesters was observed in LPS + ASA-treated animals. Unlike control, aspirin, or LPS-treated animals, LPS + ASA-treated animals accumulated relatively large amounts of unusual CoA esters, including propionyl-CoA, (iso)butyryl-CoA, beta-methylcrotonyl-CoA, and isovaleryl-CoA, metabolites of the branch chain amino acid and odd-chain fatty acid oxidation pathways. The acyl-CoA profile is similar to that obtained in patients with Reye's syndrome. Like human patients with Reye's syndrome, these rats showed hyperammonemia, compromised fatty acid oxidation, and accumulation of branched chain amino acid oxidation metabolites. Accumulation of these intermediates with LPS + ASA is a possible mechanism for the potentiation of Reye's syndrome by aspirin. These findings provide biochemical evidence that sublethal doses of LPS + ASA administered to fasted rats produces an animal model of Reye's syndrome.
Kilpatrick
L E
LE
Department of Pediatrics, University of Pennsylvania Medical School, Children's Hospital, Philadelphia 19104.
Polin
R A
RA
Douglas
S D
SD
Corkey
B E
BE
D000214:Acyl Coenzyme A / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage* / Q000009:adverse effects; D004195:Disease Models, Animal; D004347:Drug Interactions; D004731:Endotoxins / Q000008:administration & dosage* / Q000494:pharmacology; D004734:Energy Metabolism; D006801:Humans; D007657:Ketone Bodies / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012202:Reye Syndrome / Q000378:metabolism* / Q000503:physiopathology
D000214:Acyl Coenzyme A; D004731:Endotoxins; D007657:Ketone Bodies; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D001241:Aspirin