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On the Production and Disposition of Quinolinic Acid in Rat Brain and Liver Slices
Author(s) -
Speciale Carmela,
Schwarcz Robert
Publication year - 1993
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1993.tb05840.x
Subject(s) - incubation , quinolinic acid , extracellular , biochemistry , chemistry , metabolism , endogeny , endocrinology , medicine , biology , tryptophan , amino acid
The de novo production and subsequent disposition of the endogenous excitotoxin quinolinic acid (QUIN) was investigated in vitro in tissue slices from rat brain and liver. Incubation of tissue with QUIN's immediate bioprecursor 3‐hydroxyanthranilic acid (3‐HANA) in oxygenated Krebs‐Ringer buffer yielded measurable amounts of QUIN both in the tissue and in the incubation medium. Saturation was reached between 16 and 64 μ M 3‐HANA (166 pmol of QUIN formed per milligram of protein after a 60‐min incubation with 64 μ M 3‐HANA). In the brain, more QUIN was recovered from the tissue than from the incubation medium at all time points examined (5 min to 4 h). In contrast, the tissue‐to‐medium ratio for QUIN in parallel experiments with hepatic slices was ≪ 1. The disposition of newly synthesized QUIN was further elaborated in tissue slices that had been preincubated for 60 min with 64 μ M 3‐HANA. Subsequent incubation of brain tissue in fresh buffer revealed a steady but relatively slow efflux of QUIN from the cellular compartment, with >30% remaining in the tissue after a 90‐min incubation. Analogous experiments with liver slices showed that >93% of newly synthesized QUIN had entered the extracellular compartment within 30 min. Striatal and nigral slices obtained 7 days after an intrastriatal ibotenic acid injection showed severalfold increases in QUIN production compared with control tissues, in all likelihood due to astrogliosis and associated large increases in 3‐hydroxyanthranilic acid oxygenase activity. In addition, the apparent tissue‐to‐medium ratio was markedly reduced in striatal slices from lesioned animals. Taken together, these data indicate that both brain and liver cells have a rather limited capacity to retain QUIN, and that 3‐hydroxyanthranilic acid oxygenase activity is a critical determinant controlling extracellular QUIN concentrations in both organs. Changes in the activity of QUIN's biosynthetic enzyme in the brain can therefore be expected to influence the possible function of QUIN as an endogenous agonist at the N ‐methyl‐D‐aspartate receptor in health and disease.