Soman-inhibited plasma CarbE

Similar sensitivity to DAM reactivation is reported for various soman-inhibited CarbEs. Following in vitro inhibition by soman, the CarbE isoenzymes with low pi in plasma of both rat and guinea pig are partially reactivated (50-60%) by DAM within 5 min and are not further reactivated during the next 30 min (Sterri and Foimum, 1987 Sterri, 1989). The two isoenzymes in rat plasma cannot be discriminated based on the DAM reactivatability (Sterri, 1989), whereas the one with high pi (6.1) in guinea pig plasma is about half as sensitive to DAM reactivation as the other two (Sterri and Fonnum, 1987). Also, two out of three CarbE isoenzymes in rat small intestine display similar reactivatability as the plasma CarbEs (Sterri, 1989), whereas none of the three CarbE isoenzymes in guinea pig liver can be reactivated by this oxime after soman inhibition (Sterri and Foimum, 1987). The latter results correspond well with the poor effect by DAM on soman-inhibited commercial CarbEs from porcine liver (Fonnum et al., 1985). 

Toxicity of organophosphates can be potentiated 15-20-fold in rats and mice by pretreatment with a metabolite of tri-O-cresylphosphate, CBDP (2-0-cresyl)-4H-l,3,2-benzodioxa-phosphorin-2-oxide), which is an irreversible inhibitor of CarbEs. In similar studies, tetraisopropylpyrophosphoramide (iso-OMPA), or mipafox, an organophosphate-irreversible inhibitor of CarbEs, potentiates three-to fivefold the toxicity of several OPs (soman, DFP, and methylparathion) and carbamates (carbofuran, aldicarb, propoxur, and carbaryl). Inhibition of CarbEs by CBDP, iso-OMPA, or mipafox pretreatment, particularly in plasma, liver, heart, brain, and skeletal muscles, is a major contributory factor in the potentiation of toxicity of organophosphates and carbamates. Thus, the toxicity of any drug, pesticide, or other type of agent that is normally detoxified by CarbEs, could be potentiated by pre-exposure to an organophosphorus or other carboxylesterase inhibitor. 

Contrary to these findings of decreased CarbE activity increasing toxicity of many OPC, there are also data showing that increased CarbE activity can decrease toxicity of some OPC. Activity of CarbE can be increased by about 80% after repeated administration of phenobarbital to rats and mice by mechanism of enzyme induction which caused decrease in soman and tabun toxicity by 2 fold, while toxicity of sarin was not affected probably because plasma CarbE inhibited with sarin spontaneously reactivate very rapidly in vitro and in vivo with the halftimes of 18 and 120 minutes, respectively [53, 56, 66, 68],... 

In the study of mechanism of interaction of CarbE with some OPC in vitro it was found that this reaction is not irreversible, but reversible due to rapid spontaneous reactivation of inhibited CarbE [23, 53], The highest rate of spontaneous reactivation was obtained for plasma CarbE inhibited with sarin and the half time of reactivation was 18 minutes. These results were also confirmed in experiments in vivo in which rats were treated with 0.5 LD50 of soman, sarin and dichlorvos [53], Calculated half-times of reactivation for plasma CarbE of the rats treated with 0.5 LD50 dichlorvos, sarin and soman were 1.2, 2.0 and 2.7 hours, respectively. Spontaneous reactivation of CarbE hydrolyzing phenyl valerate inhibited with paraoxon in vitro was observed by Barril et al. [72],... 

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. 

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