In vivo toxic effects of 4-methoxy-5-hydroxy-canthin-6-one in zebrafish embryos via copper dyshomeostasis and oxidative stress

Guiyi Gong; Lingling Jiang; Qinghua Lin; Wenyuan Liu; Ming-Fang He; Jie Zhang; Feng Feng; Wei Qu; Ning Xie

doi:10.1016/j.cbpc.2017.11.014

In vivo toxic effects of 4-methoxy-5-hydroxy-canthin-6-one in zebrafish embryos via copper dyshomeostasis and oxidative stress

Comp Biochem Physiol C Toxicol Pharmacol. 2018 Jan:204:79-87. doi: 10.1016/j.cbpc.2017.11.014. Epub 2017 Dec 5.

Authors

Guiyi Gong¹, Lingling Jiang², Qinghua Lin¹, Wenyuan Liu³, Ming-Fang He², Jie Zhang⁴, Feng Feng⁵, Wei Qu⁶, Ning Xie⁷

Affiliations

¹ Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
² Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211800, China.
³ Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
⁴ Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 211198, China.
⁵ Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 211198, China. Electronic address: fengfeng@cpu.edu.cn.
⁶ Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 211198, China. Electronic address: popoqzh@126.com.
⁷ State Key Laboratory of Innovative Natural Medicines and TCM Injections, Jiangxi Qingfeng Pharmaceutical Co., Ltd., Ganzhou 341000, Jiangxi, China.

PMID: 29208543
DOI: 10.1016/j.cbpc.2017.11.014

Abstract

Dysfunction of copper homeostasis can lead to a host of disorders, which might be toxic sometimes. 4-Methoxy-5-hydroxy-canthin-6-one (CAN) is one of the major constituents from Picrasma quassioides and responsible for its therapeutic effects. In this work, we evaluated the toxic effect of CAN (7.5μM) on zebrafish embryos. CAN treatment decreased survival, delayed hatching time and induced malformations (loss of pigmentation, pericardial edema, as well as hematologic and neurologic abnormalities). Besides, exogenous copper supplementation rescued the pigmentation and cardiovascular defects in CAN-treated embryos. Further spectroscopic studies revealed a copper-chelating activity of CAN. Then its regulation on the expressions of copper homeostasis related genes also be analyzed. In addition, CAN lowered the total activity of SOD, elevated the ROS production and altered the oxidative related genes transcriptions, which led to oxidative stress. In conclusion, we demonstrated that CAN (7.5μM) might exert its toxic effects in zebrafish embryos by causing copper dyshomeostasis and oxidative stress. It will give insight into the risk assessment and prevention of CAN-mediated toxicity.

Keywords: 4-Methoxy-5-hydroxy-canthin-6-one; Copper homeostasis; Oxidative stress; Picrasma quassioides; Zebrafish.

MeSH terms

Animals
Copper / metabolism*
Embryo, Nonmammalian / drug effects*
Homeostasis / drug effects*
Indoles / toxicity*
Lethal Dose 50
Molecular Structure
Naphthyridines / toxicity*
Oxidative Stress / drug effects*
Zebrafish / embryology*

Substances

Indoles
Naphthyridines
Copper
nigakinone