title: Monocrotophos induces the expression and activity of xenobiotic metabolizing enzymes in pre-sensitized cultured human brain cells.
abstract: The expression and metabolic profile of cytochrome P450s (CYPs) is largely missing in human brain due to non-availability of brain tissue. We attempted to address the issue by using human brain neuronal (SH-SY5Y) and glial (U373-MG) cells. The expression and activity of CYP1A1, 2B6 and 2E1 were carried out in the cells exposed to CYP inducers viz., 3-methylcholanthrene (3-MC), cyclophosphamide (CPA), ethanol and known neurotoxicant- monocrotophos (MCP), a widely used organophosphorous pesticide. Both the cells show significant induction in the expression and CYP-specific activity against classical inducers and MCP. The induction level of CYPs was comparatively lower in MCP exposed cells than cells exposed to classical inducers. Pre-exposure (12 h) of cells to classical inducers significantly added the MCP induced CYPs expression and activity. The findings were concurrent with protein ligand docking studies, which show a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR, PXR and AHR. Similarly, the known CYP inducers- 3-MC, CPA and ethanol have also shown significantly high docking scores with all the three studied CYP regulators. The expression of CYPs in neuronal and glial cells has suggested their possible association with the endogenous physiology of the brain. The findings also suggest the xenobiotic metabolizing capabilities of these cells against MCP, if received a pre-sensitization to trigger the xenobiotic metabolizing machinery. MCP induced CYP-specific activity in neuronal cells could help in explaining its effect on neurotransmission, as these CYPs are known to involve in the synthesis/transport of the neurotransmitters. The induction of CYPs in glial cells is also of significance as these cells are thought to be involved in protecting the neurons from environmental insults and safeguard them from toxicity. The data provide better understanding of the metabolizing capability of the human brain cells against xenobiotics.
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India; Department of Biotechnology, Integral University, Lucknow, India.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Tripathi
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India; Department of Biotechnology, Integral University, Lucknow, India.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Abhishek K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Kashyap
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Jahan
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Ankita
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Metabolic and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India.
authors.forename: Sarfaraz
authors.initials: S
authors.lastname: Alam
authors.affiliation: Metabolic and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India.
authors.forename: Feroz
authors.initials: F
authors.lastname: Khan
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Khanna
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Yadav
authors.affiliation: Department of Biotechnology, Integral University, Lucknow, India.
authors.forename: Mohtshim
authors.initials: M
authors.lastname: Lohani
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Aditya B
authors.initials: AB
authors.lastname: Pant
mesh_terms: D055162:Biocatalysis / Q000187:drug effects; D001921:Brain / Q000166:cytology*; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D062105:Molecular Docking Simulation; D008999:Monocrotophos / Q000378:metabolism* / Q000633:toxicity*; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D011487:Protein Conformation; D014158:Transcription, Genetic / Q000187:drug effects; D015262:Xenobiotics / Q000378:metabolism / Q000633:toxicity
chemical_list: D009498:Neurotoxins; D015262:Xenobiotics; D008999:Monocrotophos; D003577:Cytochrome P-450 Enzyme System