Paraoxon tolerance

Recovery of AChE activity by de novo synthesi.s has been reported to be vital for tolerance to repetitive exposure to DFP in rat, especially with respect to restoration of AChE activity in skeletal muscle (Gupta et ai, 1986a Gupta and Dettbam, 1986 Dettbarn and Gupta, 1989). Also, modifications in the affinity of AChE for ACh in paraoxon-tolerant rats have been reported by Milatovic and Dettbam (1996), who observed a 20-25% increase in affinity (decrease in ATn,) for ACh by both the brain and the diaphragm AChE. 

Dettham, W-D., Yang, Z.P., Milatovic, D. (1999). Different role of carboxylesterases in toxicity and tolerance to paraoxon and DFP. Chem. Biol. Interact. 119-20 445-54. 

A total exposure of several times the acute LDs ) dose over a prolonged period can be tolerated by rodents when exposed repetitively to OP compounds such as schradan (Rider et at.. 1952), demeton (Barnes and Denz 1954a,b), disiilfoion (Brodeur and Dubois, 1964 Stavinoha ei al., 1969), DFP (Glow et al., 1966 Russel ef at., 1975), paraoxon (Weeker et at., 1977), dichlorvos (Sterri, 1981), sarin (Fonnum and Steni, 1981 Sterri, 1981), or soman (Sterri et al., 1980, 1981 Fonnum and Sterri, 1981 Sterri, 1981). For several of these compounds, the spontaneous reactivation of inhibited AChE may explain part of the tolerance. For soman, however, the tolerance cannot be related to any recovery of AChE since sornan is a completely irreversible AChE inhibitor (Coult ef /.. 1966). 

Yang, Z. R, and Detlbarn, W.-D. (1998), Prevention of tolerance to the organophosphorus anticholinesterase paraoxon with car-boxyle.stcrase inhibitors. Riochem. Pharmacol. 55, 1419-1426. 

Thomsen, R, H, and Wilson, D. K (1986). Chronic effects of paraoxon on transmitter release and the. synaptic contribution to tolerance. J. Pharmacol. Exp. Titer. 237, 6S9-694,... 

During the last decade parathion has been the most used organo-phosphorus insecticide. It has been proved to be valuable in crop protection 27). However, using this compound so much has also resulted in numerous accidental intoxications, and many have been lethal 28). In aquatic environments parathion hydrolyzes to yield p-nitro-phenol or oxidizes to yield paraoxon (25, 26). Baker (29) has shown that substituted phenols aflFect the odor quality of drinking water. p-Nitrophenol may be chlorinated at a water treatment plant to produce an odorous product. The U. S. Public Health Service has adopted 1 /xg/liter as a limit for phenolic compounds in water (10). Paraoxon is more toxic to insects and mammals than the parent compound parathion (27). The lethal dose (LD50) for male white rats is 14 mg/kg for parathion while that determined for paraoxon is only 3 mg/kg (30). Bioassay studies with fathead minnows indicated a Median Tolerance Limit (TLni) (96 hours) for parathion of 1.4 mg/liter and 0.3 mg/liter for paraoxon. 

A problem for CarbE as a scavenger for nerve gases is that VX and echothiophate are both 10,000-fold better inhibitors of AChE than CarbE. This is due to the anion attraction of ChE as described in the section "Active site," earlier in this chapter. OP-inhibited CarbE differ from OP-AChE in that they do not age. Instead, they spontaneously reactivate similar to a slow substrate. The half-life for spontaneous reactivahon of sarin-inhibited CarbE is 2h, whereas for soman or paraoxon, it is 20 h and for DFP, it is 40 h (Maxwell and Brecht, 2001). This agrees with results from a series of experiments with repetitive injection of 0.5x LD50 of soman in guinea pigs at different intervals, which demonstrated that soman was completely removed within 24 h and plasma CarbE (tribut5U inase) activity was fully recovered (Sterri et al., 1981). The slow reactivation of DEP from CarbE explains its low tolerance to repetitive administration. 

---