Anti-ChE activity

TABLE 4-3. Anti-ChE Activities of Oral HA, Donepezil, and Tacrine in Rats... 

Figure 4-3. IC50 ( jM) of anti-ChE activities of HA derivatives on AChE (rat erythroc3fte membrane) and BuChE (rat serum) over a concentration range from 1 nM to 10 nM. Data from Refs. 121 and 122.

The major gap in the available information on GA is the lack of either a subchronic or a chronic oral toxicity study from which to derive the RfD. The absence of oral data could be addressed by conducting a subchronic oral toxicity study that assesses anti-ChE activity in red blood cells (RBCs) and plasma in one or preferably two species. If further research reveals that significant toxic effects can be induced by any of the nerve agents at doses below those that cause significant ChE inhibition, additional studies should be conducted to reassess the safety of the recommended RfD for GA. 

In rats, the phrenic nerve discharge was prolonged during respiratory depression. Since the toxin F7 has a potent anti-ChE activity, it is concluded that the respiratory failure induced by toxin F7 is peripheral in origin, chiefly, if not entirely, due to its anticholinesterase activity. 

The CBs used as pesticides are N-substituted esters of carbamic acid. CBs developed in the 1950s as insect repellents were found to have insecticidal activity, leading to the development of the napthyl CBs with high anti-ChE activity and selective toxicity against insects. One example is carbaryl it is widely used because of its low toxicity to mammals and its degradability. Aldicarb, a plant systemic, is more toxic than carbaryl. A few years ago aldicarb was associated with a July 4th holiday incident when West Coast residents complained of anticholinergic symptoms after eating aldicarb-contaminated watermelon. 

The OP insecticides, as discussed elsewhere in this book, have as a primary mechanism of acute toxicity the inhibition of the critical and widespread nervous system enzyme AChE. However, the anticholinesterase (anti-ChE) potencies do not correspond with the acute toxicity levels (Chambers et a ., 1990), indicating that metabolism is an important factor in determining the overall toxicity level. The OP insecticides evolved from the chemical technologies of World War II, which were used to develop the anti-ChE nerve agents. The OP inseeticidc.s bear some chemical resemblance to these nerve agents but are generally less toxic, often require metabolic activation to display anti-ChE activity and therefore are slower to act, and usually have more complex chemical substituents. 

Studies by Hodgson and Casida (1960, 1961) were the first investigations of CM oxidation by microsomal NADPH-dependent enzymes. There is evidence that oxidation is the more important route for some CM metabolism, not only in a pharmacokinetic but also in a toxicological perspective because, unlike hydrolysis that usually generates detoxication products, oxidative metabolites often retain the CM ester bond and can sometimes have more potent anti-ChE activity (Oonnithan and Ca.sida, 1968). 

The retina has AChE and cholinergic activities (Hutchins, 1987). Choline uptake and its conversion to ACh in the rat and rabbit retina have been shown to be very active (Attcrwill ei al. 1975). As noted later, some studies indicate that retinal toxicity may be associated with anti-ChE activity, and it is of interest and possible relevance to note that the ERG responds to ACh and its agonists with an initial increase followed by a decrease in b-wave amplitude, and that anti-ChEs have similar effects. However, neurotransmission in the retina i.s complex, and at least five neurotransinitlers have been identified y-aminobutyric acid, glycine, dopamine, idolaminc, and ACh. Thus, the... 

Organophosphate-induced delayed neuropathy is unrelated to the anticholinesterase (anti-ChE) effects of OP agents because many highly potent cholinergic OPs do not cause neuropathy, and other OP compounds such a.s tri-o-cresyl phosphate (which is not used as a pesticide) have only weak anti-ChE activity but are powerful inducers of neuropathy. The enzyme involved in organo-phosphatc-induced delayed neuropathy is neuropathy target esterase—lysophospholipase (Lush et al 1998 ... 

The differences observed between chlorthiophos, carbosulfan, and other pesticides that have been examined appear to be largely due to their rate of absorption, and anti-ChE activity. These relationships were recently examined for carbaryl [1-naphthyl methylcarbamate], parathion ( 9) and thiodicarb [dimethyl N,N (thiobis[(methylimido)carbonyloxy]] bis [ethanimidothioate]] (10) in the Sprague-Dawley rat and are reviewed in this paper. 

Similar studies by Fukuto et al. have correlated chemical reactivity, anti-ChE activity, and toxicity to insects of a series of oximes of substituted acetophenones and benzalde-hydes with the free-energy parameters, F, ° R, ir, and Excellent correlation was obtained between these... 

In the example of the benzaldehyde oximes, the addition of Hansch s tt constant to the equation was necessary for corre lation with the anti-ChE activity. ... 

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