Chlorpyrifos oxon potentiates diacylglycerol-induced extracellular signal-regulated kinase (ERK 44/42) activation, possibly by diacylglycerol lipase inhibition.
Chlorpyrifos oxon (CPO) activates extracellular signal-regulated kinase (ERK 44/42) in Chinese hamster ovary (CHOK1) cells but the mechanism is not defined. This study tests the hypothesis that diacylglycerol (DAG) is the secondary messenger responsible for CPO-induced ERK 44/42 activation. It is known that DAG is sequentially hydrolyzed by DAG lipase and monoacylglycerol (MAG) lipase, both of which are organophosphate sensitive. Inhibition of these enzymes might therefore lead to the accumulation of DAG and MAG, of which only DAG is a secondary messenger. The experiments show that treatment of CHOK1 cells with CPO significantly inhibits DAG/MAG lipase activity and elevates cellular DAG levels. Pretreatment of CHOK1 cells with CPO or a carbamate known to be a DAG lipase inhibitor, followed by treatment with a cell-permeable DAG (1,2-dihexanoyl-sn-glycerol), results in synergistic activation of ERK 44/42. CPO-potentiated DAG-induced ERK 44/42 activation is both time and concentration dependent. This activation is blocked by inhibitors of protein kinase C and mitogen-activated protein kinase kinase, suggesting that these enzymes are important in CPO/DAG cellular signaling. Activation by a stable DAG analogue (phorbol ester) was not altered by CPO, suggesting that DAG metabolism is the probable target for CPO-potentiated DAG-induced ERK 44/42 activation. These observations support the hypothesis that CPO potentiates DAG signaling in CHOK1 cells by inhibiting a CPO-sensitive DAG lipase, thereby providing a potential mechanism of toxicity not associated with acetylcholinesterase inhibition.
Bomser
Joshua A
JA
Environmental Chemistry and Toxicology Laboratory, University of California, Berkeley, California 94720-3112, USA. bomser.1@osu.edu
Quistad
Gary B
GB
Casida
John E
JE
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D004390:Chlorpyrifos / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006224:Cricetinae; D003512:Cyclohexanones / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D011549:Pseudomonas / Q000187:drug effects / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
D003512:Cyclohexanones; D004075:Diglycerides; D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; D020928:Mitogen-Activated Protein Kinases; D008071:Lipoprotein Lipase; D004390:Chlorpyrifos; D013755:Tetradecanoylphorbol Acetate