In vivo and in silico evaluations of survival and cardiac developmental toxicity of quinolone antibiotics in zebrafish embryos (Danio rerio).

Affiliation

Han Y(1), Ma Y(2), Yao S(1), Zhang J(3), Hu C(4).
Author information:
(1)Division of Antibiotics, Institute for Chemical Drug Control, National Institutes for Food and Drug Control, Beijing, 102629, China.
(2)Department of Pharmacology, NHC Key Laboratory of Biotechnology of Antibiotics, Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
(3)Department of Pharmacology, NHC Key Laboratory of Biotechnology of Antibiotics, Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [Email]
(4)Division of Antibiotics, Institute for Chemical Drug Control, National Institutes for Food and Drug Control, Beijing, 102629, China. Electronic address: [Email]

Abstract

Quinolones are ranked as the second most commonly used class of antibiotics in China, despite their adverse clinical and environmental effects. However, information on their cardiac developmental toxicity to zebrafish is limited. This study investigates the relationships between different quinolone structures and toxicity in zebrafish embryos using in vivo and in silico methods. All of the experimentally tested quinolones show cardiac developmental toxicity potential and present mortality and teratogenic effects in a dose-dependent manner. Theoretically, the acute toxicity values predicted using quantitative structure-toxicity relationship (QSTR) modeling based on previously reported LC50 values are in good agreement with the in vivo results. Further investigation demonstrates that the hormetic concentration response of some quinolones may be related to methylation on the piperazine ring at the C-7 position. The amino group at the C-5 position, the methylated or ethylated piperazine group at the C-7 position, halogens at the C-8 position and a cyclopropyl ring at N1 position may be responsible for cardiac developmental toxicity. In terms of survival (key ecological endpoint), the naridine ring is more toxic than the quinoline ring. This combined approach can predict the acute and cardiac developmental toxicity of other quinolones and impurities.