Chiarugi A, Carpenedo R, Moroni F
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
J Neurochem. 1996 Aug;67(2):692-8. doi: 10.1046/j.1471-4159.1996.67020692.x.
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.
为了研究体内喹啉酸和犬尿喹啉酸合成的调控机制，我们进行了以下评估：(a) 通过测量小鼠血液和大脑中犬尿氨酸主要代谢产物3-羟基犬尿氨酸、邻氨基苯甲酸和3-羟基邻氨基苯甲酸的含量，来研究给予犬尿氨酸后的代谢情况；(b) 犬尿氨酸羟化酶的选择性抑制剂（间硝基苯甲酰）丙氨酸和犬尿氨酸酶的选择性抑制剂（邻甲氧基苯甲酰）丙氨酸对该代谢的影响；(c) （邻甲氧基苯甲酰）丙氨酸对肝脏犬尿氨酸酶和3-羟基犬尿氨酸酶活性的影响。从这些实验得出的结论如下：(a) 给予的犬尿氨酸在大脑中优先通过羟基化代谢，在周围组织中通过水解代谢；(b) 犬尿氨酸羟化酶抑制剂（间硝基苯甲酰）丙氨酸引起大脑犬尿氨酸代谢的预期变化，如3-羟基犬尿氨酸减少，犬尿喹啉酸增加；(c) 犬尿氨酸酶抑制剂（邻甲氧基苯甲酰）丙氨酸增加了细胞毒性化合物3-羟基犬尿氨酸的脑内浓度，且意外地未降低喹啉酸的直接前体3-羟基邻氨基苯甲酸的脑内浓度。综上所述，这些实验表明，全身给予犬尿氨酸羟化酶抑制剂是一种合理的方法，可以增加大脑中犬尿喹啉酸的含量，并降低细胞毒性犬尿氨酸代谢产物（如3-羟基犬尿氨酸和喹啉酸）的含量。
