title: The toxicity of mixtures of specific organophosphate compounds is modulated by paraoxonase 1 status.
abstract: Most chemical exposures involve complex mixtures. The role of paraoxonase 1 (PON1) and the Q192R polymorphism in the detoxication of individual organophosphorous (OP) compounds has been well-established. The extent to which PON1 protects against a given OP is determined by its catalytic efficiency. We used a humanized transgenic mouse model of the Q192R polymorphism to demonstrate that PON1 modulates the toxicity of OP mixtures by altering the activity of another detoxication enzyme, carboxylesterase (CaE). Chlorpyrifos oxon (CPO), diazoxon (DZO), and paraoxon (PO) are potent inhibitors of CaE, both in vitro and in vivo. We hypothesized that exposure of mice to these OPs would increase their sensitivity to the CaE substrate, malaoxon (MO), and that the degree of effect would vary among PON1 genotypes if the OP was a physiologically relevant PON1 substrate. When wild-type mice were exposed dermally to CPO, DZO, or PO and then, after 4 h, to different doses of MO, the toxicity of MO was increased compared to mice that received MO alone. The potentiation of MO toxicity by CPO and DZO was higher in PON1 knockout mice, which are less able to detoxify CPO or DZO. Potentiation by CPO was higher in Q192 mice than in R192 mice due to the decreased ability of PON1(Q192) to detoxify CPO. Potentiation by DZO was similar in the Q192 and R192 mice, due to their equivalent effectiveness at detoxifying DZO. PO exposure resulted in equivalent potentiation of MO toxicity among all four genotypes. These results indicate that PON1 status modulates the ability of CaE to detoxicate OP compounds from specific mixed insecticide exposures. PON1 status can also impact the capacity to metabolize drugs or other CaE substrates following insecticide exposure.
authors.affiliation: Department of Medicine and Genome Sciences, University of Washington, Seattle, WA, USA. tobycole@u.washington.edu
authors.forename: Toby B
authors.initials: TB
authors.lastname: Cole
authors.forename: Karen
authors.initials: K
authors.lastname: Jansen
authors.forename: Sarah
authors.initials: S
authors.lastname: Park
authors.forename: Wan-Fen
authors.initials: WF
authors.lastname: Li
authors.forename: Clement E
authors.initials: CE
authors.lastname: Furlong
authors.forename: Lucio G
authors.initials: LG
authors.lastname: Costa
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase / Q000737:chemistry / Q000235:genetics*; D043182:Carboxylesterase / Q000737:chemistry; D004390:Chlorpyrifos / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D005838:Genotype; D007306:Insecticides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000633:toxicity*; D010261:Paraoxon / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D007306:Insecticides; D009943:Organophosphorus Compounds; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; C000912:diazoxon; D043182:Carboxylesterase; D043303:Aryldialkylphosphatase; D004390:Chlorpyrifos; D010261:Paraoxon