The comparative analysis of gastrointestinal toxicity of azithromycin and 3'-decladinosyl azithromycin on zebrafish larvae.

The most commonly reported side effect of azithromycin is gastrointestinal (GI) disorders, and the main acid degradation product is 3'-Decladinosyl azithromycin (impurity J). We aimed to compare the GI toxicity of azithromycin and impurity J on zebrafish larvae and investigate the mechanism causing the differential GI toxicity. Results of our study showed that the GI toxicity induced by impurity J was higher than that of azithromycin in zebrafish larvae, and the effects of impurity J on transcription in the digestive system of zebrafish larvae were significantly stronger than those of azithromycin. Additionally, impurity J exerts stronger cytotoxic effects on GES-1 cells than azithromycin. Simultaneously, impurity J significantly increased ghsrb levels in the zebrafish intestinal tract and ghsr levels in human GES-1 cells compared to azithromycin, and ghsr overexpression significantly reduced cell viability, indicating that GI toxicity induced by azithromycin and impurity J may be correlated with ghsr overexpression induced by the two compounds. Meanwhile, molecular docking analysis showed that the highest -CDOCKER interaction energy scores with the zebrafish GHSRb or human GHSR protein might reflect the effect of azithromycin and impurity J on the expression of zebrafish ghsrb or human ghsr. Thus, our results suggest that impurity J has higher GI toxicity than azithromycin due to its greater ability to elevate ghsrb expression in zebrafish intestinal tract.