title: Cholinesterase inhibition and alterations of hepatic metabolism by oral acute and repeated chlorpyrifos administration to mice.
abstract: Chlorpyrifos (CPF) is a broad spectrum organophosphorus insecticide bioactivated in vivo to chlorpyrifos-oxon (CPFO), a very potent anticholinesterase. A great majority of available animal studies on CPF and CPFO toxicity are performed in rats. The use of mice in developmental neurobehavioural studies and the availability of transgenic mice warrant a better characterization of CPF-induced toxicity in this species. CD1 mice were exposed to a broad range of acute (12.5-100.0mg/kg) and subacute (1.56-25mg/kg/day from 5 to 30 days) CPF oral doses. Functional and biochemical parameters such as brain and serum cholinesterase (ChE) and liver xenobiotic metabolizing system, including the biotransformation of CPF itself, have been studied and the no observed effect levels (NOELs) identified. Mice seem to be more susceptible than rats at least to acute CPF treatment (oral LD(50) 4.5-fold lower). The species-related differences were not so evident after repeated exposures. In mice a good correlation was observed between brain ChE inhibition and classical cholinergic signs of toxicity. After CPF-repeated treatment, mice seemed to develop some tolerance to CPF-induced effects, which could not be attributed to an alteration of P450-mediated CPF hepatic metabolism. CPF-induced effects on hepatic microsomal carboxylesterase (CE) activity and reduced glutathione (GSH) levels observed at an early stage of treatment and then recovered after 30 days, suggest that the detoxifying mechanisms are actively involved in the protection of CPF-induced effects and possibly in the induction of tolerance in long term exposure. The mouse could be considered a suitable experimental model for future studies on the toxic action of organophosphorus pesticides focused on mechanisms, long term and age-related effects.
authors: Drug Research and Evaluation Dept, Istituto Superiore di Sanità, V le Regina Elena 299, Rome, Italy. cometa@iss.it
authors: Maria Francesca
authors: MF
authors: Cometa
authors: Franca Maria
authors: FM
authors: Buratti
authors: Stefano
authors: S
authors: Fortuna
authors: Paola
authors: P
authors: Lorenzini
authors: Maria Teresa
authors: MT
authors: Volpe
authors: Laura
authors: L
authors: Parisi
authors: Emanuela
authors: E
authors: Testai
authors: Annarita
authors: A
authors: Meneguz
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D006900:Hydroxylation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D011728:Pyridones / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D002800:Cholinesterase Inhibitors; D011728:Pyridones; D013739:Testosterone; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; C012587:3,5,6-trichloro-2-pyridinol; D000110:Acetylcholinesterase; D005978:Glutathione; D004390:Chlorpyrifos