Aliesterases

Su M, Kinoshita FK, Frawley JP, et al. 1971. Comparative inhibition of aliesterases and cholinesterase in rats fed eighteen organophosphorus insecticides. Toxicol Appl Pharmacol 20 241 -249. 

Adaptive Enzyme Theory. The aliesterases are largely found in the microsomes of rat liver cells (44). Recently Hart and Fouts (51,52, 67-69) have presented evidence that in vivo administration of chlordan or chemically related DDT stimulates the activity of hepatic microsomal drug-metabolizing enzymes, as evidenced by proliferation of smooth-surfaced endoplasmic reticulum (SER) which was first noted with phenobarbital. Several reviews of hepatic drug metabolism... 

The use of a rat study for developing an RfD for GA is complicated by the fact that rodents have a much lower RBC-AChE activity level compared to humans (Ellin, 1981). By itself, this could cause rats to be relatively more sensitive than humans to anticholinesterase compounds however, the lower RBC-AChE activity may be offset by the presence of ahesterases in the blood of rats. Aliesterases, which are not found in human blood plasma, are known to bind to and, therefore, reduce the toxicity of GB, and a similar mechanism may operate in the case of GA. Other species differences, such as in the rates of aging of the GA-ChE complex, in the rates of synthesis of plasma-ChE in the liver, and in the levels of AChE in the nervous system (see Ivanov et al., 1993) may also result in difference between species in sensitivity to GA. Data are insufficient to more fuUy evaluate these possibihties. There is httle human acute toxicity data that can be compared with the available rat data however, acute toxicity data for primates in general (see Table 2) suggests that humans are likely to be more sensitive than rats. Therefore, for the purpose of this assessment, the standard EPA method will be followed which assumes that humans can be as much as ten times more sensitive to a chemical than laboratory animals. 

These differences in RBC-ChE activity may affect a species sensitivity to a particular organophosphate compound. At the same time, the relative amonnt of plasma cholinesterase and other compounds in the blood that can bind to the organophosphate agents mnst also be considered. As noted above, rodents, but not humans, have high levels of aliesterases in the blood (Cohen et al., 1971). These compounds may provide rats and mice with a higher level of resistance to anticholinesterase componnds to which they bind, such as GB, but not to others snch as VX (Fonnnm and Sterri, 1981). 

Sarin was involved in terrorist attacks in Japan (Okumura et al, 2003 Okudera, 2002). The increase in sympathetic and parasympathetic tone results in tachycardia, ST-segment modulation (Abraham et al, 2001), and arrhythmia. Inhibition of cholinesterase within the neuroeffector junction also affects nerve impulse transmission by direct action. Direct action on muscarinic or nicotinic ACh receptors (Somani et al, 1992) is observed when the blood level of sarin exceeds the micromolar level. Sarin inhibits RBC-AChE 80-100% as well as plasma-BChE between 30 and 50% (Grob and Harvey, 1958). It also binds to aliesterase, an enzyme that contributes to ester-link hydrolysis. 

Clement, J.G. (1984). Role of aliesterase in organophosphate poisoning. Fundam. Appl. Toxicol. 4 S96-105. 

De Jong L.P., Van Dijk C. (1984). Formation of soman (1,2,2-trimethylpropyl methylphosphonofluoridate) via fluoride-induced reactivation of soman-inhibited aliesterase in rat plasma. Biochem. Pharmacol. 33 663-9. 

Pond, A.L., Chambers, H.W., Chambers, J.E. (1995). Qrgano-phosphate detoxication potential of various rat tissues via A-esterase and aliesterase activities. Toxicol. Lett. 70 245-52. 

Mendel, B., Myers, D.K. (1953). Aliesterase inhibition by tri-ortho-cresy-phosphate. Biochem. J. 53 Xvi. 

Myers, D.K. (1952). Competition of the aliesterase in rat serum with the pseudo cholinesterase for diisopropyl fluo-rophosphonate. Science 115 568-70. 

Chambers JE and Chambers HW (1990) Time course of inhibition of acetylcholinesterase and aliesterases following parathion and paraoxon exposures in rats. Toxicology and Applied Pharmacology 103 420-429. 

Clement JG (1989) Role of aliesterases in organophosphate poisoning. Fundamental and Applied Toxicology 4 S94-S105. 

Clement JG. Importance of aliesterase as a detoxification mechanism for soman (pinacolyl methylphosphono-fiuoridate) in mice. Biochem Pharmacol, 1984 33 3807-3811. 

Boskovic, B., Jokanovic, M., and Maksimovic, M., Effects of sarin, soman and tabun on plasma and brain aliesterase activity in the rat, In M. Brzin, EA Barnard and D. Sket (Eds), Cholinesterases - Fundamental and applied aspects, Walter de Gruyter, Berlin-New York, 365-374,1984. 

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