Department of Genetics and Cytology, V.N. Karazin Kharkiv National University, Kharkiv, Ukraine.
Department of Biopharmacy, Medical University of Lublin, Chodzki 4a/01a, 20-093, Lublin, Poland.
Neurotox Res. 2018 Aug;34(2):324-331. doi: 10.1007/s12640-018-9891-5. Epub 2018 Apr 4.
Kynurenic acid (KYNA) is one of the metabolites of evolutionary conserved tryptophan (Trp)/kynurenine (Kyn) metabolic pathway. Elevation of KYNA contributes to development of psychosis in schizophrenia but attenuates neurodegeneration in Drosophila model of Huntington's disease. We have reported that KYNA increased lethality of pupae of wild-type flies, but not of vermilion (v) mutants with impaired formation of Kyn from Trp, suggesting that KYNA toxicity depends on its interaction with downstream Kyn metabolites [i.e., 3-hydroxykynurenine (3-HK) and/or xanthurenic acid (XA)]. The present study aimed to further explore the mechanisms of KYNA-induced lethality by the assessment of KYNA effect on pupae of two Drosophila mutants: cinnabar (cn), characterized by higher KYNA and lower 3-HK production, and cardinal (cd), characterized by higher 3-HK and XA levels compared to wild-type flies. Our microarray datamining revealed that the gene expression pattern of enzymes forming Trp/Kyn pathway stands in line with previously reported developmental changes in KYNA, 3-HK, and XA concentrations in wild-type and mutant flies. Administration of KYNA increased pupae lethality in cd, but not in cn mutants. Present data suggest that toxic effect of exogenous KYNA depends on the presence of 3-HK and/or XA. This is further supported by our finding that early stages of Drosophila development are associated with a positive expression pattern of genes encoding sulfotransferases, enzymes that are inhibited by KYNA and are involved in detoxification of XA. Alternatively, the toxic effect of KYNA might depend on anti-proliferative effects of KYNA.
犬尿酸（KYNA）是进化保守的色氨酸（Trp）/犬尿氨酸（Kyn）代谢途径的代谢产物之一。KYNA 的升高有助于精神分裂症的精神病发展，但减轻亨廷顿病果蝇模型中的神经退行性变。我们已经报道 KYNA 增加了野生型蝇蛹的致死率，但不能增加色氨酸形成犬尿氨酸受损的朱砂（v）突变体的致死率，这表明 KYNA 毒性取决于其与下游犬尿氨酸代谢物的相互作用[即 3-羟基犬尿氨酸（3-HK）和/或黄尿酸（XA）]。本研究旨在通过评估 KYNA 对两种果蝇突变体蛹的影响，进一步探讨 KYNA 诱导致死的机制：朱砂（cn），其特征是 KYNA 水平较高，3-HK 产量较低，而 cardinal（cd），其特征是 3-HK 和 XA 水平高于野生型蝇。我们的微阵列数据分析显示，形成 Trp/Kyn 途径的酶的基因表达模式与先前报道的野生型和突变型蝇中 KYNA、3-HK 和 XA 浓度的发育变化一致。KYNA 的给药增加了 cd 突变体而不是 cn 突变体的蛹致死率。目前的数据表明，外源性 KYNA 的毒性作用取决于 3-HK 和/或 XA 的存在。这进一步得到了我们的发现的支持，即果蝇发育的早期阶段与编码磺基转移酶的基因的阳性表达模式相关，磺基转移酶是被 KYNA 抑制并参与 XA 解毒的酶。或者，KYNA 的毒性作用可能取决于 KYNA 的抗增殖作用。
