Network Toxicology Prediction and Molecular Docking-based Strategy to Explore the Potential Toxicity Mechanism of Metformin Chlorination Byproducts in Drinking Water


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Abstract

Background:Metformin (MET), a worldwide used drug for treating type 2 diabetes but not metabolized by humans, has been found with the largest amount in the aquatic environment. Two MET chlorination byproducts, including Y and C, were transformed into drinking water during chlorination. However, the potential toxicity of the byproducts in hepatotoxicity and reproduction toxicity remains unclear.

Methods:The TOPKAT database predicted the toxicological properties of metformin disinfection by-products. The targets of metformin disinfection by-products were mainly obtained from the PharmMapper database, and then the targets of hepatotoxicity and reproductive toxicity were screened from GeneCards. The overlapping targets of toxic component targets and the hepatotoxicity or reproduction toxicity targets were regarded as the key targets. Then, the STRING database analyzed the key target to construct a protein-protein interaction network (PPI) and GO, and KEGG analysis was performed by the DAVID platform. Meanwhile, the PPI network and compound- target network were constructed by Cytoscape 3.9.1. Finally, Discovery Studio 2019 software was used for molecular docking verification of the two toxic compounds and the core genes.

Results:Y and C exhibited hepatotoxicity, carcinogenicity, and mutagenicity evaluated by TOPKAT. There were 22 potential targets relating to compound Y and hepatotoxicity and reproduction toxicity and 14 potential targets relating to compound C and hepatotoxicity and reproduction toxicity. PPI network analysis showed that SRC, MAPK14, F2, PTPN1, IL2, MMP3, HRAS, and RARA might be the key targets; the KEGG analysis indicated that compounds Y and C caused hepatotoxicity through Hepatitis B, Pathways in cancer, Chemical carcinogenesis-reactive oxygen species, Epstein-Barr virus infection; compound Y and C caused reproduction toxicity through GnRH signaling pathway, Endocrine resistance, Prostate cancer, Progesterone-mediated oocyte maturation. Molecular docking results showed that 2 compounds could fit in the binding pocket of the 7 hub genes.

Conclusion:This study preliminarily revealed the potential toxicity and possible toxicity mechanism of metformin disinfection by-products and provided a new idea for follow-up research.

About the authors

Gui-Hong Zhang

School of Pharmaceutical Science, Liaoning University

Email: info@benthamscience.net

Hongwei Liu

Department of Head and Neck Surgery, Cancer Hospital of China Medical University

Email: info@benthamscience.net

Mei-Hua Liu

School of Pharmaceutical Science, Liaoning University

Email: info@benthamscience.net

Yang-Cheng Liu

School of Pharmaceutical Science, Liaoning University

Email: info@benthamscience.net

Jia-Qi Wang

School of Pharmaceutical Science, Liaoning University

Email: info@benthamscience.net

Yang Wang

School of Pharmaceutical Science, Liaoning University

Email: info@benthamscience.net

Xin Wang

School of Pharmaceutical Science, Liaoning University

Email: info@benthamscience.net

Zheng Xiang

School of Pharmaceutical Science, Liaoning University

Email: info@benthamscience.net

Wei Liu

School of Pharmaceutical Science, Liaoning University

Author for correspondence.
Email: info@benthamscience.net

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