Oxidation organophosphates metabolism

Still another experimental route to introducing otherwise excluded molecules into the brain is to chemically modify them so that they are lipophilic and therefore can passively diffuse. The brain, just as most other organs and tissues of the body, has enzymes to metabolize or biotransform metabolites in order to use and then get rid of them. Many of these pathways are oxidative. A reduced species or derivative which is lipophilic can enter the brain by simple passive diffusion there to be oxidatively transformed into an active state. Compounds which have been tested in animals include derivatives of 2-PAM (an antidote for organophosphate insecticide poisoning) and phenylethylamine (similar to amphetamine type molecules). Figure 5 illustrates the general concept behind this method. 

Esterase activity is important in both the detoxication of organophosphates and the toxicity caused by them. Thus brain acetylcholinesterase is inhibited by organophosphates such as paraoxon and malaoxon, their oxidized metabolites (see above). This leads to toxic effects. Malathion, a widely used insecticide, is metabolized mostly by carboxylesterase in mammals, and this is a route of detoxication. However, an isomer, isomalathion, formed from malathion when solutions are inappropriately stored, is a potent inhibitor of the carboxylesterase. The consequence is that such contaminated malathion becomes highly toxic to humans because detoxication is inhibited and oxidation becomes important. This led to the poisoning of 2800 workers in Pakistan and the death of 5 (see chap. 5 for metabolism and chap. 7 for more details). 

Mineral oils and PAOs found in hydraulic fluids are not anticipated to undergo appreciable metabolism. There is some evidence that organophosphate esters are oxidized by cytochrome P450 and then form conjugates and are excreted. 

This enzyme is important in its ability to metabolize organophosphates such as paraoxon and the association of the enzyme with high-density lipoprotein (HDL) and the protection of low-density lipoproteins from the effects of oxidative stress (Costa et al. 1990 Feingold et al. 1998 Costa and Furlong 2002 Costa et al. 2005 Costa, Vitalone, et al. 2005). The enzyme exists in several polymorphisms and it is synthesized mainly in the liver. The enzyme activity can be measured using paraoxon as substrate (Hasselwander et al. 1998). Although the measurement of the enzyme has been used mainly in monitoring the effects of pesticides, more recently the enzyme has received increased attention as a measure of hepatic injury (Gil et al. 1994 Hernandez et al. 1997 Ferre et al. 2002) and in the study of causation of atherosclerosis. 

Oxidative -demethylation is a pathway involved in the metabolism of some amide-substituted organophosphates. Dicrotophos is A-demethylated to monocrotophos via the iV-methylol derivative [156,157]. Monocrotophos, itself an active inhibitor of cholinesterase used in pest control, is further A-demethylated to its iV-methylol and finally to the unsubstituted amide [157]. This latter step is of only minor significance [158]. The principal degradative metabolite of dicrotophos, dimethyl phosphate, produced by hydrolysis of the vinyl-phosphate linkage was found to exceed the production of 0-demethylmonocrotophos by a ratio of approximately 4 lwhile only trace amounts of the iV-demethylated metabolite were detected [158]. 

It was determined that substitution of the 5 -position of thiophene resulted in improved activity, most notably against organophosphate resistant two spotted spider mites (Table VI). This series of substituted thienyl derivatives shows surprisingly little variation when tested against a susceptible strain of TSM. It is assumed that the unsubstituted thienyl moiety is susceptible to metabolic oxidation, and that simple substitution (for example, methyl) at the 5 -position stabilizes the compound toward these oxidative processes. 

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