Comparative analysis of gastrointestinal toxicity induced by cefazolin and its impurities in zebrafish
Objective This study employed a zebrafish model to comprehensively assess and compare the gastrointestinal toxicity induced by cefazolin,impurity F,and impurity A,shedding light on the underlying mechanisms.Methods Real-time observation of zebrafish larvae's gastrointestinal emptying under a fluorescence microscope allowed the evaluation of toxicity responses to cefazolin,impurity F,and impurity A.Structural relationships among the three compounds were analyzed.Genome expression patterns associated with gastrointestinal toxicity reactions were elucidated by means of RNA-seq technology.Molecular docking assessed the binding affinity between the compounds and the bile salt export pump(BSEP)protein.Results Impurity F exhibited significantly higher gastrointestinal emptying capacity compared to cefazolin,while impurity A demonstrated notably lower emptying capacity than cefazolin.The MMTD structure emerged as the primary toxic functional group responsible for cefazolin-induced gastrointestinal toxicity.RNA-seq analysis unveiled 45 significantly differentially expressed genes shared between the impurity F group and the cefazolin and impurity A groups.These genes were predominantly enriched in the mineral absorption and bile secretion pathways,with the expression of the abcb11b gene closely linked to gastrointestinal toxicity reactions.Molecular docking results indicated that impurity F had a stronger affinity for zebrafish BSEP than cefazolin,while cefazolin exhibited a higher binding affinity compared to impurity A.Conclusion Clinical gastrointestinal toxicity reactions attributed to cefazolin sodium may be associated with impurity F in the product.The assessment of the binding affinity of the drug and the impurities to the BSEP protein offered insights into variations in gastrointestinal toxicity reactions caused by the impurities in cefazolin sodium.This study provided a theoretical foundation for evaluating the production process and quality control of cefazolin sodium.
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