title: Interaction of ethanol and the organophosphorus insecticide parathion.
abstract: Phosphorothioate insecticides such as parathion (O,O-diethyl-O-p-nitrophenyl phosphorothioate) undergo P450-dependent oxidative desulfuration, leading to both activation and detoxification of these compounds. Consequently, alterations in P450-dependent oxidative desulfuration may affect the acute toxicities of these insecticides. In the present study, pretreatment of mice with 15% ethanol in the drinking water for 6 days antagonized the acute toxicity of parathion, but not its toxic metabolite paraoxon (O,O-diethyl-O-p-nitrophenyl phosphate), suggesting that ethanol affected the oxidative desulfuration of this insecticide. The presence of ethanol within hepatic microsomal incubations did not alter the P450-dependent formation of paraoxon (activation) and p-nitrophenol (detoxification), although p-nitrophenol levels were increased in the presence of ethanol as a result of inhibition of its biotransformation to 4-nitrocatechol by CYP2E1. Ethanol exposure reduced hepatic pyruvate levels, but had no effect on levels of lactate, isocitrate, alpha-ketoglutarate, and malate. Calculation of cytosolic NAD+/NADH and cytosolic NADP+/NADPH redox ratios did not reveal any detectable difference in redox state between control and ethanol-treated mice. Since ethanol did not alter directly the P450-dependent activation or detoxification of parathion, and did not decrease NADPH levels, ethanol's antagonism of the acute toxicity of parathion may result from reduced availability of O2.
authors.affiliation: Department of Pharmacology and Toxicology, University of Medicine and Dentistry of New Jersey, Newark 07103-2714, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: O'Shaughnessy
authors.forename: L G
authors.initials: LG
authors.lastname: Sultatos
mesh_terms: D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D007306:Insecticides / Q000633:toxicity*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010261:Paraoxon / Q000378:metabolism; D010278:Parathion / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity*
chemical_list: D007306:Insecticides; D000431:Ethanol; D010278:Parathion; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D010261:Paraoxon