Changes in quinolinic acid production and its related enzymes following D-galactosamine and lipopolysaccharide-induced hepatic injury.
Increases in quinolinic acid (QUIN), a neurotoxic L-tryptophan metabolite, have been observed in human serum and cerebrospinal fluid and in animal models of severe hepatic injury. The aim of this study was to evaluate the changes in QUIN accumulation and its related enzymes after acute hepatic injury induced by D-galactosamine and endotoxin. Gerbils were given an intraperitoneal injection of pyrogen-free saline alone as control, lipopolysaccharide (LPS) alone (150 ng/kg), D-galactosamine alone (500 mg/kg) or a combination of D-galactosamine with LPS. Concentrations of QUIN, its related metabolites, and related enzyme activities were determined. D-Galactosamine treatment significantly decreased activities of hepatic aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase) resulting in increased QUIN concentrations in serum and tissues. The magnitude of QUIN responses was markedly increased by endotoxin due to the increased availability of L-kynurenine, a rate-limiting substrate for QUIN synthesis. Further, infiltration of monocytes/macrophages, which is a possible major source of QUIN production in the liver, was shown by immunohistochemistry after hepatic injury induced by D-galactosamine and endotoxin. Increased serum QUIN concentrations are probably due to the increased substrate availability and the decreased activity of aminocarboxymuconate-semialdehyde decarboxylase in the liver, accompanying the increased monocyte/macrophage infiltration into the liver after hepatic injury.
Ohashi
Hazuki
H
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Saito
Kuniaki
K
Fujii
Hidehiko
H
Wada
Hisayasu
H
Furuta
Nobuyuki
N
Takemura
Masao
M
Maeda
Satoshi
S
Seishima
Mitsuru
M
D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism; D004731:Endotoxins / Q000378:metabolism; D005688:Galactosamine / Q000737:chemistry* / Q000494:pharmacology; D005849:Gerbillinae; D006801:Humans; D007150:Immunohistochemistry; D007737:Kynurenine / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000293:injuries; D008264:Macrophages / Q000378:metabolism; D008956:Models, Chemical; D009000:Monocytes / Q000378:metabolism; D011749:Pyrogens / Q000378:metabolism; D017378:Quinolinic Acid / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
D004731:Endotoxins; D008070:Lipopolysaccharides; D011749:Pyrogens; D007737:Kynurenine; D005688:Galactosamine; D002262:Carboxy-Lyases; C024396:aminocarboxymuconate-semialdehyde decarboxylase; D017378:Quinolinic Acid