Miller Christine L
MillerBio, 6508 Beverly Rd, Baltimore, MD 21239, USA.
Eur Neuropsychopharmacol. 2015 Mar;25(3):435-40. doi: 10.1016/j.euroneuro.2014.12.001. Epub 2014 Dec 18.
Two kynurenine metabolites, 3-hydroxykynurenine and 3-hydroxyanthranilic acid, are known to inhibit melanin polymer formation in in vitro reactions catalyzed by tyrosinase. The present study expands that finding to include inhibition of chlorpromazine-stimulated melanin formation from the endogenous melanin precursor adrenochrome. Several kynurenine pathway metabolites tested had no measurable effect on the reaction: tryptophan, kynurenine, kynurenic acid, quinolinic acid and nicotinic acid. However, at a concentration of 0.5mM in a pH 7.4 reaction mix, 3-hydroxykynurenine exerted~72% inhibition on product formation and the same concentration of 3-hydroxyanthranilic acid caused complete inhibition. Two other classes of antipsychotic drugs were evaluated in this paradigm, represented by olanzapine and minocycline. Although the adrenochrome reaction of both drugs was strongly inhibited by 3-hydroxyanthranilic acid, 3-hydroxykynurenine inhibited product formation from only the minocycline reaction. The results are discussed in terms of the well-studied kynurenine pathway upregulation in psychotic disorders and how such upregulation may either influence the efficacy of antipsychotic drug treatment or relate to the mechanism of action of these drugs.
已知两种犬尿氨酸代谢产物，即3 - 羟基犬尿氨酸和3 - 羟基邻氨基苯甲酸，在酪氨酸酶催化的体外反应中可抑制黑色素聚合物的形成。本研究将这一发现扩展至包括对氯丙嗪刺激内源性黑色素前体肾上腺色素生成黑色素的抑制作用。所测试的几种犬尿氨酸途径代谢产物对该反应无显著影响：色氨酸、犬尿氨酸、犬尿喹啉酸、喹啉酸和烟酸。然而，在pH 7.4的反应混合物中，当浓度为0.5mM时，3 - 羟基犬尿氨酸对产物形成的抑制率约为72%，相同浓度的3 - 羟基邻氨基苯甲酸则导致完全抑制。在该实验模式中还评估了另外两类抗精神病药物，以奥氮平和米诺环素为代表。尽管3 - 羟基邻氨基苯甲酸强烈抑制了这两种药物的肾上腺色素反应，但3 - 羟基犬尿氨酸仅抑制了米诺环素反应的产物形成。将根据在精神疾病中已得到充分研究的犬尿氨酸途径上调情况，以及这种上调如何影响抗精神病药物治疗的疗效或与这些药物的作用机制相关来讨论这些结果。
