Liver toxicity of macrolide antibiotics in zebrafish
Zhang, Miao-qing1,2,3,4,5; Chen, Bo5; Zhang, Jing-pu5; Chen, Ning4; Liu, Chun-zhao2,3; Hu, Chang-qin6
Source PublicationTOXICOLOGY
AbstractMacrolide antibiotics (macrolides) are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections, but macrolides also expose people to the risk of adverse events include hepatotoxicity. Here, we report the liver toxicity of macrolides with different structures in zebrafish. The absorption, distribution, metabolism, excretion and toxicology (ADMET) parameters of macrolide compounds were predicted and contrasted by utilizing in silico analysis. Fluorescence imaging and Oil Red O stain assays showed all the tested macrolide drugs induced liver degeneration, changed liver size and liver steatosis in larval zebrafish. Through RNA-seq analysis, we found seven co-regulated differentially expressed genes (co-DEGs) associated with metabolism, apoptosis and immune system biological processes, and two co-regulated significant pathways including amino sugar and nucleotide sugar metabolism and apoptosis signaling pathway. We found that only fosab of seven co-DEGs was in the two co-regulated significant pathways. fosab encoded proto-oncogene c-Fos, which was closely associated with liver diseases. The whole-mount in situ hybridization showed high transcription of c-Fos induced by macrolide compounds mainly in the liver region of zebrafish larvae. Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) leakage assays revealed that macrolides exerts significant cytotoxic effects on L02 cells. qRT-PCR and western blot analysis demonstrated macrolides also promoted human c-Fos expression in L02 cells. The c-Fos overexpression significantly reduced cell viability by using CCK-8 assay. These data indicate that hepatotoxicity induced by macrolides may be correlated with c-Fos expression activated by these compounds. This study may provide a biomarker for the further investigations on the mechanism of hepatotoxicity induced by macrolide drugs with different structures, and extend our understanding for improving rational clinical application of macrolides.
KeywordLiver toxicity Macrolides ADMET RNA-seq analysis Differentially expressed genes c-Fos
Funding ProjectNational Major Scientific and Technological Special Project for "Significant New Drugs Development"[2017ZX09101001-007]
WOS Research AreaPharmacology & Pharmacy ; Toxicology
WOS SubjectPharmacology & Pharmacy ; Toxicology
Funding OrganizationNational Major Scientific and Technological Special Project for "Significant New Drugs Development"
WOS IDWOS:000558135000003
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Document Type期刊论文
Corresponding AuthorChen, Ning; Liu, Chun-zhao; Hu, Chang-qin
Affiliation1.China Resources Sanjiu Med & Pharmaceut Co Ltd, Postdoctoral Sci Res Workstn, Shenzhen 518110, Peoples R China
2.Chinese Acad Sci, Postdoctoral Mobile Res Stn, Inst Proc Engn, State Key Lab Biochem Engn, Beijing 100190, Peoples R China
3.Univ Chinese Acad Sci, Sch Chem Engn, Beijing 100190, Peoples R China
4.Shenzhen China Resources Gosun Pharmaceut Co Ltd, Shenzhen 518049, Peoples R China
5.Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biotechnol, Beijing 100050, Peoples R China
6.Natl Inst Food & Drug Control, Beijing 100050, Peoples R China
Recommended Citation
GB/T 7714
Zhang, Miao-qing,Chen, Bo,Zhang, Jing-pu,et al. Liver toxicity of macrolide antibiotics in zebrafish[J]. TOXICOLOGY,2020,441:12.
APA Zhang, Miao-qing,Chen, Bo,Zhang, Jing-pu,Chen, Ning,Liu, Chun-zhao,&Hu, Chang-qin.(2020).Liver toxicity of macrolide antibiotics in zebrafish.TOXICOLOGY,441,12.
MLA Zhang, Miao-qing,et al."Liver toxicity of macrolide antibiotics in zebrafish".TOXICOLOGY 441(2020):12.
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