title: Activation of extracellular signal-regulated kinases (ERK 44/42) by chlorpyrifos oxon in Chinese hamster ovary cells.
abstract: Acetylcholinesterase inhibition explains most but not all of the toxicological manifestations of exposure to the major organophosphorus insecticide chlorpyrifos (CP) and its metabolically activated form chlorpyrifos oxon (CPO); CPO is also reported to interact with muscarinic acetylcholine receptors and alter secondary messenger status. We find that CP and CPO activate extracellular signal-regulated kinases (ERK 44/42) in both wild-type (CHOK1) and human muscarinic receptor-expressing Chinese hamster ovary cells (CHO-M2). The degree of ERK 44/42 activation on treatment with 50 microM CPO for 40 minutes is 2- to 3-fold compared with control cells and is both concentration- and time-dependent. CP is at least 2-fold less potent than CPO as an activator of ERK 44/42 and the hydrolysis products 3,5,6-trichloropyridinol and diethyl phosphate are not activators. ERK 44/42 activation by CPO is insensitive to the protein kinase A inhibitor H-89, but is completely abolished by the phosphatidylinositol 3-kinase (P13-K) inhibitor wortmannin, the protein kinase C (PKC) inhibitor GF-109203X, and the mitogen-activated extracellular signal-regulated protein kinase kinase (MEK) inhibitor PD 098059. Therefore, CPO activates the ERK 44/42 signaling cascade in CHOK1 cells via a pathway dependent on P13-K, PKC, and MEK but not requiring PKA or the human M2 muscarinic receptor. In summary we find that CPO activates a mammalian signal transduction cascade involved in cell growth and differentiation. This occurs through a pathway common to growth factors and mitogens, consistent with a receptor-mediated event. However, CPO may also inhibit an enzyme involved in signal transduction. The specific target of CPO leading to the activation of ERK 44/42 and the potential effects of this activation on cell function remain to be determined.
authors.affiliation: Department of Environmental Science, Policy and Management, University of California, Berkeley 94720-3112, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bomser
authors.forename: J E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000818:Animals; D016466:CHO Cells; D004390:Chlorpyrifos / Q000031:analogs & derivatives* / Q000494:pharmacology; D006224:Cricetinae; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D011976:Receptors, Muscarinic; D011994:Recombinant Proteins; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D004390:Chlorpyrifos