Monocrotophos induces the expression and activity of xenobiotic metabolizing enzymes in pre-sensitized cultured human brain cells

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 carr...

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Published in:	PloS one Vol. 9; no. 3; p. e91946
Main Authors:	Tripathi, Vinay K, Kumar, Vivek, Singh, Abhishek K, Kashyap, Mahendra P, Jahan, Sadaf, Pandey, Ankita, Alam, Sarfaraz, Khan, Feroz, Khanna, Vinay K, Yadav, Sanjay, Lohani, Mohtshim, Pant, Aditya B
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 24-03-2014 Public Library of Science (PLoS)
Subjects:	3-Methylcholanthrene Agrochemicals Biocatalysis - drug effects Biology and Life Sciences Biotechnology Brain Brain - cytology Brain research Carcinogens Cell Line, Tumor Computer and Information Sciences Cyclophosphamide Cytochrome Cytochrome P-450 Cytochrome P-450 Enzyme System - chemistry Cytochrome P-450 Enzyme System - genetics Cytochrome P-450 Enzyme System - metabolism Cytochrome P450 Docking Dopamine Drugs Enzymes Ethanol Exposure Gene expression Gene Expression Regulation, Enzymologic - drug effects Glial cells Humans Laboratories Machinery and equipment Metabolism Molecular Docking Simulation Monocrotophos Monocrotophos - metabolism Monocrotophos - toxicity Neuronal-glial interactions Neurons Neurotoxicity Neurotoxins - metabolism Neurotoxins - toxicity Neurotransmission Neurotransmitters Parkinson's disease Parkinsons disease Pesticides Physiological aspects Protein Conformation Regulators Rodents Strong interactions (field theory) Studies Toxicity Toxicology Transcription, Genetic - drug effects Xenobiotics Xenobiotics - metabolism Xenobiotics - toxicity India
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Summary:	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.
Bibliography:	Competing Interests: The corresponding author Dr. Aditya B Pant is currently acting as Academic Editor for PLoS ONE. This does not alter the authors' adherence to PLOS ONE Editorial Policies and criteria. Conceived and designed the experiments: ABP. Performed the experiments: VKT VK AKS MPK SJ SA FK AP. Analyzed the data: VKT VK AKS MPK SJ SA FK VKK SY ML AP ABP. Contributed reagents/materials/analysis tools: ABP FK VKK SY ML. Wrote the paper: VKT ABP FK.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0091946