KYNURENINE DISPOSITION IN BLOOD AND BRAIN OF MICE - EFFECTS OF SELECTIVE INHIBITORS OF KYNURENINE HYDROXYLASE AND OF KYNURENINASE

To study the regulation of the synthesis of quinolinic and kynurenic a cids in vivo, we evaluated (a) the metabolism of administered kynureni ne by measuring the content of its main metabolites 3-hydroxykynurenin e, anthranilic acid, and 3-hydroxyanthranilic acid in blood and brain of mice; (b) the effects of (m-nitrobenzoyl) alanine, a selective inhi bitor of kynurenine hydroxylase and of (o-methoxybenzoyl) alanine, a s elective inhibitor of kynureninase, on this metabolism; and (c) the ef fects of (o-methoxybenzoyl) alanine on liver kynureninase and 3-hydrox ykynureninase activity. The conclusions drawn from these experiments a re (a) the disposition of administered kynurenine preferentially occur s through hydroxylation in brain and through hydrolysis in peripheral tissues; (b) (m-nitrobenzoyl)alanine, the inhibitor of kynurenine hydr oxylase, causes the expected changes in brain kynurenine metabolism, s uch 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-hydroxykynur enine, and unexpectedly does not reduce brain concentration of 3-hydro xyanthranilic acid, the direct precursor of quinolinic acid. Taken tog ether, the experiments suggest that the systemic administration of a k ynurenine hydroxylase inhibitor is a rational approach to increase the brain content of kynurenate and to decrease that of cytotoxic kynuren ine metabolites, such as 9-hydroxykynurenine and quinolinic acid.