title: Monocrotophos Induces the Expression of Xenobiotic Metabolizing Cytochrome P450s (CYP2C8 and CYP3A4) and Neurotoxicity in Human Brain Cells.
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.
authors.affiliation: Department of Animal Science and Biotechnology, Chonbuk National University, Jeonju, 561-756, Republic of Korea. vinaytripathi2007@gmail.com.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Tripathi
authors.affiliation: Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo, Sao Paulo, SP, Brazil.
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: Ankita
authors.initials: A
authors.lastname: Pandey
authors.affiliation: In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Pankhi
authors.initials: P
authors.lastname: Vatsa
authors.affiliation: Research Cell, Amity University, Lucknow, India.
authors.forename: Anupam
authors.initials: A
authors.lastname: Dhasmana
authors.affiliation: Department of Biochemistry, Dr. Ram Manohar Lohia Avadh University, Faizabad, India.
authors.forename: Rajat Pratap
authors.initials: RP
authors.lastname: Singh
authors.affiliation: Department of Molecular Genetics, L. V. Prasad Eye Institute, Hyderabad, India.
authors.forename: Sri Hari Chandan
authors.initials: SHC
authors.lastname: Appikonda
authors.affiliation: Department of Animal Science and Biotechnology, Chonbuk National University, Jeonju, 561-756, Republic of Korea.
authors.forename: Inho
authors.initials: I
authors.lastname: Hwang
authors.affiliation: Research and Scientific Studies Unit, Collage of Nursing and Allied Health Science, Jazan University, Jazan, Saudi Arabia.
authors.forename: Mohtashim
authors.initials: M
authors.lastname: Lohani
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000201:enzymology* / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D000090702:Constitutive Androstane Receptor; D003520:Cyclophosphamide / Q000494:pharmacology; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008024:Ligands; D015227:Lipid Peroxidation / Q000187:drug effects; D015162:Micronucleus Tests; D062105:Molecular Docking Simulation; D008999:Monocrotophos / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D000077297:Pregnane X Receptor; D014176:Protein Biosynthesis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015262:Xenobiotics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000090702:Constitutive Androstane Receptor; D008024:Ligands; D009498:Neurotoxins; D000077297:Pregnane X Receptor; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; D051028:bcl-2-Associated X Protein; D008999:Monocrotophos; D003520:Cyclophosphamide; D045304:Cytochromes c; D002374:Catalase; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D020169:Caspases
keywords: Apoptosis; Cytochrome P450s; Genotoxicity; Human glial cells; Human neural cells; Monocrotophos; Xenobiotic metabolism