Organophosphates carboxylesterases inhibition

The capability of organophosphates to inhibit pseudocholinesterases and carboxylesterases without causing clinical signs provides a mechanism by which... 

Carboxylesterases Esterases that hydrolyze organic compounds with carboxylester bonds. Carboxylesterases that are inhibited by organophosphates (OPs) belong to the category EC 3.1.1.1 in the lUB classification of enzymes. 

Cross-tolerance between disulfoton and another organophosphate, chlorpyrifos, was observed in mice (Costa and Murphy 1983b). Because of this cross-tolerance, a benefit is derived as a result of this interaction. In the same study, propoxur-tolerant mice were tolerant to disulfoton but not vice versa. Propoxur (a carbamate) is metabolized by carboxylesterases, and these enzymes are inhibited in disulfoton-tolerant animals disulfoton-tolerant animals are more susceptible to propoxur and/or carbamate insecticides than are nonpretreated animals. In another study, disulfoton-tolerant rats were tolerant to the cholinergic effects of octamethyl pyrophosphoramide (OMPA) but not parathion (McPhillips 1969a, 1969b). The authors were unable to explain why the insecticides OMPA and parathion caused different effects. 

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). 

The term potentiation is then reserved for those cases where both compounds have appreciable intrinsic toxicity, such as in the case of malathion and EPN. Malathion has a low mammalian toxicity due primarily to its rapid hydrolysis by a carboxylesterase. EPN (Figure 9.6) another organophosphate insecticide, causes a dramatic increase in malathion toxicity to mammals at dose levels, which, given alone, cause essentially no inhibition of acetylcholinesterase. The increase in toxicity as a result of coadministration of these two toxicants is the result of the ability of EPN, at low concentrations, to inhibit the carboxylesterase responsible for malathion degradation. 

Malathion is an organophosphate cholinesterase inhibitor that is hydrolyzed by plasma carboxylesterases much faster in humans than in insects, thereby providing a therapeutic advantage in treating pediculosis (Chapter 7 Cholinoceptor-Activating Cholinesterase-Inhibiting Drugs). Malathion is available as a 0.5% lotion (Ovide) that should be applied to the hair when dry and the hair then combed to remove nits and lice after 4-6 hours. 

Tissue esterases have been divided into two classes the A-type esterases, which are insensitive, and the B-type esterases, which are sensitive to inhibition by organo-phosphorus esters. The A esterases include the arylesterases, whereas the B esterases include cholinesterases of plasma, acetylcholinesterases of erythrocytes and nervous tissue, carboxylesterases, lipases, and so on. The nonspecific arylesterases that hydrolyze short-chain aromatic esters are activated by Ca2+ ions and are responsible for the hydrolysis of certain organophosphate triesters such as paraoxon (Figure 10.10B). 

The inhibition by other organophosphate compounds of the carboxylesterase which hydrolyzes malathion is a further example of xenobiotic interaction resulting from irreversible inhibition because, in this case, the enzyme is phosphorylated by the inhibitor. A second type of inhibition involving organophosphorus insecticides involves those containing the P=S moiety. During CYP activation to the esterase-inhibiting oxon, reactive sulfur is released that inhibits CYP isoforms by an irreversible interaction with the heme iron. As a result, these chemicals are inhibitors of the metabolism of other xenobiotics, such as carbaryl and fipronil, and are potent inhibitors of the metabolism of steroid hormones such as testosterone and estradiol. 

See also Carboxylesterases Cholinesterase Inhibition Organophosphate Poisoning, Delayed Neurotoxicity Organophosphates. 

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. 

See also A-Esterases Carboxylesterases Cholinesterase Inhibition Neurotoxicity Organophosphates Pesticides. 

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