title: Organophosphate agents induce plasma hypertriglyceridemia in mouse via single or dual inhibition of the endocannabinoid hydrolyzing enzyme(s).
abstract: Diverse serine hydrolases including endocannabinoid metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have been suggested as secondary targets for organophosphate (OP) agents to exert adverse toxic effects such as lipid homeostasis disruption. The goal of this investigation is to verify that a major OP insecticide fenitrothion (FNT) induces plasma hypertriglyceridemia through the inhibition of FAAH and/or MAGL in comparison with that elicited by isopropyl dodecylfluorophosphonate (IDFP), a potent FAAH/MAGL inhibitor. Fasted mice were treated intraperitoneally with FNT or IDFP and were subsequently sacrificed for evaluations of plasma triglyceride (TG) levels and liver FAAH/MAGL activities. Plasma TG levels were significantly enhanced by the FNT or IDFP treatment (1.7- or 4.8-fold, respectively) compared with that of vehicle control. The IDFP exposure reduced the liver FAAH and MAGL activities, whereas the FNT exposure led to the preferential FAAH inhibition. The brain acetylcholinesterase was almost unaffected by the FNT or IDFP treatment, thus leading to no neurotoxic sign. Intriguingly, the TG elevations were averted by concomitant administration with the cannabinoid receptor antagonist AM251. The present findings suggest that OP agents induce plasma hypertriglyceridemia in mouse through single or dual inhibition of FAAH or/and MAGL, apparently leading to overstimulation of cannabinoid signal regulating energy metabolism.
authors.affiliation: Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
authors.forename: Himiko
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Noro
authors.affiliation: Department of Chemistry and Biomolecular Science, Gifu University, Gifu 501-1193, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Koketsu
authors.affiliation: Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kamijima
authors.affiliation: Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan; Faculty of Applied Bioscience, Tokyo University of Agriculture, Setagayaku, Tokyo 156-8502, Japan. Electronic address: mt204882@nodai.ac.jp.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tomizawa
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005278:Fenitrothion / Q000633:toxicity*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006868:Hydrolysis; D015228:Hypertriglyceridemia / Q000097:blood / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control; D007306:Insecticides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000187:drug effects / Q000378:metabolism; D014280:Triglycerides / Q000097:blood*; D015854:Up-Regulation; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000110:Acetylcholinesterase; D000581:Amidohydrolases; D015415:Biomarkers; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005278:Fenitrothion; D058851:GPI-Linked Proteins; D007306:Insecticides; D008994:Monoacylglycerol Lipases; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D014280:Triglycerides; D000099252:Fatty Acid Amide Hydrolases; C103505:AM 251; C548245:Ache protein, mouse
keywords: Fatty acid amide hydrolase; Fenitrothion; Monoacylglycerol lipase; Triglyceride