Toxic Effects of Cephalosporins with Specific Functional Groups as Indicated by Zebrafish Embryo Toxicity Testing
- Authors
- Zhang, J., Qian, J., Tong, J., Zhang, D., and Hu, C.Q.
- ID
- ZDB-PUB-130722-7
- Date
- 2013
- Source
- Chemical Research in Toxicology 26(8): 1168-81 (Journal)
- Registered Authors
- Zhang, Jing-pu
- Keywords
- none
- MeSH Terms
-
- Animals
- Anti-Bacterial Agents/chemistry
- Anti-Bacterial Agents/toxicity*
- Cardiovascular System/drug effects
- Cardiovascular System/growth & development
- Cephalosporins/chemistry
- Cephalosporins/toxicity*
- Embryo, Nonmammalian/drug effects*
- Embryo, Nonmammalian/metabolism
- Models, Theoretical
- Nervous System/drug effects
- Nervous System/growth & development
- Notochord/drug effects
- Notochord/growth & development
- Phenotype
- Stereoisomerism
- Water/chemistry
- Zebrafish/growth & development*
- PubMed
- 23848171 Full text @ Chem. Res. Toxicol.
Cephalosporins, a kind of derivatives of 7-aminocephalosporanic acid (7-ACA) are potent antibacterial agents. The toxicity prediction of these compounds is of considerable importance in new drug development. The zebrafish embryo toxicity testing was thought to be suitable for evaluation of the toxic property of cephalosporins. Here, five kinds of cephalosporins and their isomers were used for investigation of the toxic functional groups of cephalosporins and for further evaluation of the efficacy of zebrafish embryo toxicity testing. Computational chemistry methods were also used to study the conformations of the stereoisomers of cephalosporins in aqueous solution to explore the relationship between the stereoisomers and the experimental results of toxicity tests on zebrafish embryos. Our results suggest that both the C-7 and C-3 substituents of cephalosporins are toxic functional groups. The toxic functional groups increase the toxic reaction of 7-ACA and can induce variable abnormal phenotypes in zebrafish embryo toxicity testing. The embryonic toxicities of cephalosporins were involved in organogenesis, mainly in development of the cranial nerve, cardiovascular system, notochord and abdomen, and pigment formation; those tissues and organs are derived from ectoderm, mesoderm and endoderm. The theoretical calculations showed a strong negative correlation between topological polar surface area (TPSA) values and the toxic effect, which indicated that molecular polarity may be crucial to the toxic effects of the isomers of cephalosporins. The concept of toxic functional groups may help us understanding safety difference of cephalosporins.