Natural products have been developed as therapeutic agents for various disease including cancer in the drug discovery area. However, the potential toxicity of natural products could be a big huddle to develop the drug candidates. To overcome this limitation, the development of high-contents screening method to give the information about toxic mechanism are needed. Here, we suggest the pathway-sensing method to evaluate the cellular stress for the natural compounds using imaging analysis. Several transcriptional factors including AP-1, P53, Nrf2, and NFkb which are regulated during cellular stress response including cell proliferation, apoptosis, oxidative stress, and inflammation. To screen the cellular stress response, we constructed the established HepG2 cell lines to express the luminescence and GFP when only this transcriptional factors are activated using the transcription response element. Using pathway-sensing hepatocytes, we screened the toxic effects for the wide ranges of twenty natural compounds including flavonoid, polycyclic, di-/ter-period, and quinoid and quantitative changes were examined by imaging analysis. Several natural compounds including apigenin, the potential hepatotoxic compounds cause the cytotoxic effect mediated by AP-1, and P53 pathways and we can classify the mode of action for the natural compounds using this system. Our results suggest that the pathway-sensing hepatocytes is suitable for screening the hepatotoxicity and could give critical information about molecular mechanisms to initiate the cellular stress. This approaches can be used to build up the adverse outcome pathways (AOP) to unravel the key events associated with liver injury for natural compounds.

Mechanism-based toxicity screening of natural compounds based on high-throughput approaches

ACS Fall 2020 Virtual Meeting

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