title: Kynurenine disposition in blood and brain of mice: effects of selective inhibitors of kynurenine hydroxylase and of kynureninase.
abstract: To study the regulation of the synthesis of quinolinic and kynurenic acids in vivo, we evaluated (a) the metabolism of administered kynurenine by measuring the content of its main metabolites 3-hydroxykynurenine, anthranilic acid, and 3-hydroxyanthranilic acid in blood and brain of mice; (b) the effects of (m-nitrobenzoyl)alanine, a selective inhibitor of kynurenine hydroxylase and of (o-methoxybenzoyl) alanine, a selective inhibitor of kynureninase, on this metabolism; and (c) the effects of (o-methoxybenzoyl)alanine on liver kynureninase and 3-hydroxykynureninase activity. The conclusions drawn from these experiments are (a) the disposition of administered kynurenine preferentially occurs through hydroxylation in brain and through hydrolysis in peripheral tissues; (b) (m-nitrobenzoyl)alanine, the inhibitor of kynurenine hydroxylase, causes the expected changes in brain kynurenine metabolism, such as a decrease of 3-hydroxykynurenine, and an increase of kynurenic acid; and (c) (o-methoxybenzoyl)alanine, the kynureninase inhibitor, increases brain concentration of the cytotoxic compound 3-hydroxykynurenine, and unexpectedly does not reduce brain concentration of 3-hydroxyanthranilic acid, the direct precursor of quinolinic acid. Taken together, the experiments suggest that the systemic administration of a kynurenine hydroxylase inhibitor is a rational approach to increase the brain content of kynurenate and to decrease that of cytotoxic kynurenine metabolites, such as 3-hydroxykynurenine and quinolinic acid.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Chiarugi
authors.forename: R
authors.initials: R
authors.lastname: Carpenedo
authors.forename: F
authors.initials: F
authors.lastname: Moroni
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D062367:ortho-Aminobenzoates / Q000378:metabolism
chemical_list: C095159:2-methoxybenzoylalanine; D004791:Enzyme Inhibitors; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; D006867:Hydrolases; C021480:kynureninase; D000409:Alanine