Role of PON1 in Modulating OP Exposures
The dose response curves for the PON1 deficient mice are dramatically changed for dermal exposure to diazoxon (next slide) but much less so to exposure to the parent compound diazinon. PON1-/- mice lacking both PON1 genes were killed by dermal exposures (4 mg/kg) that had no measurable inhibition of brain cholinesterase in normal mice as well as by half that dose. Mice exposed to one-fourth the dose (1 mg/kg) of diazoxon exhibited significant signs of OP intoxication. On the other hand, the differences in sensitivity to the parent compound diazinon were less dramatic (following slide). These observations took us back to one of our earlier papers that included a literature survey of the levels of oxon in residues (Yuknavage et al. 1997, slide after next) and re-emphasized the importance of the PON1 genetic variability in modulating exposure to the oxon component as well as a role in detoxifying the parent compound.
(Li W.-F., L.G. Costa, R.J. Richter, T. Hagen, D.M. Shih, A. Tward, A.J. Lusis and C.E. Furlong. 2000. Catalytic efficiency determines the in vivo efficacy of PON1 for detoxifying organophosphates. Pharmacogenetics 10:767-780.)