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Monocrotophos Induces the Expression of Xenobiotic Metabolizing Cytochrome P450s (CYP2C8 and CYP3A4) and Neurotoxicity in Human Brain Cells

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Abstract

Expression of various cytochrome P450s (CYPs) in mammalian brain cells is well documented. However, such studies are hampered in neural/glial cells of human origin due to nonavailability of human brain cells. To address this issue, we investigated the expression and inducibility of CYP2C8 and CYP3A4 and their responsiveness against cyclophosphamide (CPA) and organophosphorus pesticide monocrotophos (MCP), a known developmental neurotoxicant in human neural (SH-SY5Y) and glial (U373-MG) cell lines. CPA induced significant expression of CYP2C8 and CYP3A4 in both types of cells in a time-dependent manner. Neural cell line exhibited relatively higher constitutive and inducible expression of CYPs than the glial cell line. MCP exposure alone could not induce the significant expression of CYPs, whereas the cells preexposed to CPA showed a significant response to MCP. Similar to the case of CPA induced expressions, neural cells were found to be more vulnerable than glial cells. Our data indicate differential expressions of CYPs in cultured human neural and glial cell lines. The findings were synchronized with protein ligand docking studies, which showed a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR and PXR. Similarly, the known CYP inducer CPA has also shown significant high docking scores with the two studied CYP regulators. We also observed a significant induction in reactive oxygen species (ROS), lipid peroxides (LPO), micronucleus (MN), chromosomal aberration (CA), and reduction in reduced glutathione (GSH) and catalase following the exposure of MCP. Moreover, the expressions of apoptotic markers such as caspase-3, caspase-9, Bax, and p53 were significantly upregulated, whereas the levels of antiapoptotic marker, Bcl2, was downregulated after the exposure of MCP in both cell lines. These findings confirm the involvement of ROS-mediated oxidative stress, which subsequently triggers apoptosis pathways in both human neural (SH-SY5Y) and glial (U373-MG) cell lines following the exposure of MCP.

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Acknowledgments

This work was carried out with the support of a grant from the Next-Generation BioGreen 21 Program (Project No. PJ011101) and a grant for FTA issues (Project No. PJ01017003) of Rural Development Administration, Republic of Korea.

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Authors and Affiliations

  1. Department of Animal Science and Biotechnology, Chonbuk National University, Jeonju, 561-756, Republic of Korea

    Vinay Kumar Tripathi & Inho Hwang

  2. Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo, Sao Paulo, SP, Brazil

    Vivek Kumar

  3. In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India

    Ankita Pandey & Pankhi Vatsa

  4. Research Cell, Amity University, Lucknow, India

    Anupam Dhasmana

  5. Department of Biochemistry, Dr. Ram Manohar Lohia Avadh University, Faizabad, India

    Rajat Pratap Singh

  6. Department of Molecular Genetics, L. V. Prasad Eye Institute, Hyderabad, India

    Sri Hari Chandan Appikonda

  7. Research and Scientific Studies Unit, Collage of Nursing and Allied Health Science, Jazan University, Jazan, Saudi Arabia

    Mohtashim Lohani

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  1. Vinay Kumar Tripathi
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Tripathi, V.K., Kumar, V., Pandey, A. et al. Monocrotophos Induces the Expression of Xenobiotic Metabolizing Cytochrome P450s (CYP2C8 and CYP3A4) and Neurotoxicity in Human Brain Cells. Mol Neurobiol 54, 3633–3651 (2017). https://doi.org/10.1007/s12035-016-9938-7

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