Zebrafish as a new model for drug metabolism and high content screen of natural product

In recent years, zebrafish has become an increasingly used model in the field of drug screening. Our recent study addressed drug absorption and metabolism in zebrafish embryos and larvae. LCMS/MS was used to identify and profile the metabolites of icaritin glycoside derivatives, which are prenylated flavonoid compounds, in zebrafish larvae. The result showed that the metabolic pathway involving the enzymatic removal of the sugar moiety of these compounds to produce the free aglycone, which is subsequently conjugated by sulfation, glucuronidation, or methylation or in different combinations [1]. Moreover, transcriptomic profiling identified 51 unique mRNA transcripts that belong to several key enzymes involved in phase I drug metabolism and phase II drug metabolism enzymes [1]. The result supports the functional similarity of drug metabolism systems in zebrafish and mammals [1]. Furthermore, a structure-activity relationship analysis of antiangiogenesis activities of a series of methoxyflavone derivatives using zebrafish assay indicated that sinensetin with a methoxylated group at the C3 position offers a stronger antiangiogenesis activity, whereas the absence of a methoxylated group at the C8 position offers lower lethal toxicity in addition to enhancing the antiangiogenesis activity [2]. In addition, zebrafish behavioural assays have shown promise for the discovery of neuroactive compounds such as quercetin, indoles containing analogues and tetramethylpyrazine analogues [3 – 4]. Taken together, our findings demonstrated that zebrafish has proven to be a suitable model for in vivo high content drug screening, and for simultaneous determination of multiple parameters, including behaviour, selectivity, and toxicity. Zebrafish screen of natural products has the potential to identify reproducible, higher potency and lower toxic agents for healthcare in the future.

Keywords: Chinese medicine, zebrafish, neurodegeneration, vascular disease, drug metabolism

References:

[1] Li, Z.H. et al. (2011) Mol BioSyst 7(7): 2128 – 38.

[2] Lam, I.K. et al. (2012) Mol Nutr and Food Res 56(6): 945 – 56.

[3] Cui, W. et al. (2013) Br J of Pharmacol 68(5): 1201 – 14.

[4] Cui, G.Z. et al. (2013) Int J of Cardio 168(2): 1349 – 59.