NUDT15 polymorphism in healthy children with Bai nationality in Yunnan of China.

BACKGROUND: Thiopurine methyltransferase (TPMT) polymorphism is one of the causes of the toxicity of thiopurines, but this is rarely seen in Asian populations. Rather, the nucleoside diphosphate-linked X-component motif 15 (NUDT15) gene is frequently linked to mercaptopurine (MP) intolerance and myelotoxicity in children with acute lymphoblastic leukemia (ALL) in East Asians; however, little is known about the NUDT15 polymorphism in healthy children, especially in ethnic minorities in China. METHODS: A total of 162 cases of healthy children with Bai nationality were enrolled for NUDT15 genotyping. RESULTS: Three coding variants were identified in the NUDT15 gene including rs186364861, rs746071566 and rs116855232. Notably, the rs746071566 and rs116855232 in NUDT15 showed much higher frequencies in healthy children with Bai nationality compared with healthy East Asian populations, suggesting a concentrated distribution of these variants in the Bai ethnic group. CONCLUSIONS: This finding reveals the genetic polymorphism of NUDT15 in children with Chinese Bai nationality, providing a biological genetic background for the individualized therapy of thiopurines for children with Bai nationality in China.

Hyoscyamine induces developmental toxicity by disrupting metabolism in zebrafish embryo (Danio rerio).

Hyoscyamine is a kind of tropane alkaloids, which exists in several plants of the family Solanaceae. However, the mechanism underlying such hyoscyamine toxic effects during early development remains unclear. In this study, an untargeted metabolomics approach was used to investigate the toxic mechanisms of hyoscyamine in zebrafish embryos. The LC10 and MNLC of hyoscyamine in zebrafish embryos were determined to be 350 and 313 µg/mL, respectively. Moreover, hyoscyamine exposure increased the accumulation of ROS and MDA, and altered the activity of antioxidant enzymes (CAT, SOD, and GSH) in zebrafish embryos. After exposure, the embryos were extracted, derivatized and analyzed by UHPLC-Q-Orbitrap-HRMS for 3551 metabolites to identify 38 significantly changed metabolites based on the VIP, p value, and fold change results. Metabolic pathways associated with those metabolites were identified using MetaboAnalyst 5.0 as follows: pyrimidine metabolism, purine metabolism, histidine metabolism, beta-Alanine metabolism, and glutathione metabolism. These results suggested that hyoscyamine exposure to zebrafish embryos exhibited marked metabolic disturbance. Such significant perturbations of important metabolites within crucial biochemical pathways may have biologically hazardous effects on zebrafish embryos induced by hyoscyamine.

Scopoletin Induced Metabolomic Profile Disturbances in Zebrafish Embryos.

Scopoletin, a typical example of a coumarin compound, exists in several Artemisia species and other plant genera. However, the systemic metabolic effects induced by scopoletin remain unclear. In the present study, we evaluated the metabolic profiles in scopoletin-exposed zebrafish embryos using UHPLC-Q-Obitrap-HRMS combined with multivariate analysis. Compared with the control group, 33 metabolites in scopoletin group were significantly upregulated, while 27 metabolites were significantly downregulated. Importantly, scopoletin exposure affected metabolites mainly involved in phosphonate and phosphinate metabolism, vitamin B6 metabolism, histidine metabolism, sphingolipid metabolism, and folate biosynthesis. These results suggested that scopoletin exposure to zebrafish embryos exhibited marked metabolic disturbance. This study provides a perspective of metabolic impacts and the underlying mechanism associated with scopoletin exposure.