Metabolism of organophosphates

Murphy SD. 1982. Toxicity of hepatic metabolism of organophosphate insecticides in developing rats. In Hunt VR, Smith MK, Worth D, eds. Banbury report, Vol. II. Environmental factors in hiunan growth and development symposium, November 1-4, 1981. Cold Spring Harbor, NY Cold Spring Harbor Laboratory, 125-136. 

Studies directly examining the metabolism of organophosphate ester hydraulic fluids in animals are limited. One study identified metabolites in ether extracts of bile obtained from rabbits given single,... 

McLean, S., M. Sameshina, T. Katayama, J. Iwata, C.E. Olney, and K.L. Simpson. 1984. A rapid method to determine microsomal metabolism of organophosphate pesticides. Bull. Japan. Soc. Sci. Fish. 50 1419-1423. 

Riviere, J.E. Chang, S.K. Transdermal penetration and metabolism of organophosphate insecticides. 

No studies were located that examined the toxicokinetics of mineral oil, organophosphate ester, or polyalphaolefin hydraulic fluids in humans or animals, with the exception of a study examining absorption in rats after exposure to a hydraulic fluid containing 99.9% cyclotriphosphazene (Kinkead and Bashe 1987) and the absorption and metabolism of Reolube HYD46, another organophosphate hydraulic fluid (Ciba-Geigy 1985). This section, therefore, discusses available information on the toxicokinetics of major components of these classes of hydraulic fluids or of materials that maybe expected to display similar toxicokinetic properties based on similar physical and chemical characteristics. It should be emphasized that many hydraulic fluids are complex mixtures of chemicals that may include some chemicals which may not share toxicokinetic properties with the major components. 

Use of the muscle relaxant succinylcholine, which is metabolized by plasma cholinesterase, is contraindicated in cases of organophosphate poisoning (Giurini et al. 1986). 

Phosphinates are a class of organophosphorus compounds, the metabolism of which has received less attention than that of phosphates (see above) or phosphorothioates and P-halidc compounds (see below). Many phosphinates are rapid but transient inhibitors of acetylcholinesterase and carboxyl-esterases. And like organophosphates and phosphonates, phosphinates are substrates of arylesterases (EC 3.1.1.2). This is exemplified by 4-nitrophen-yl ethyl(phenyl)phosphinate (9.62), whose (-)-enantiomer was hydrolyzed by rabbit serum arylesterase almost 10 times faster than the (+)-enantiomer [133],... 

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). 

Many xenobiotics contain alkyl groups, such as the methyl (-CH3) group, attached to atoms of O, N, and S. An important step in the metabolism of many of these compounds is replacement of alkyl groups by H, as shown in Figure 7.6. These reactions are carried out by mixed-function oxidase enzyme systems. Examples of these kinds of reactions with xenobiotics include O-dealky-lation of methoxychlor insecticides, N-dealkylation of carbary 1 insecticide, and S-dealkylation of dimethyl mercaptan. Organophosphate esters (see Chapter 18) also undergo hydrolysis, as shown in Reaction 7.3.12 for the plant systemic insecticide demeton ... 

Fumes B, Schlenk D. Extrahepatic metabolism of carbamate and organophosphate thioether compounds by the flavin-containing monooxygenase and cytochrome P450 systems. Drug Metab Dispos 2005 33 214—218. 

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. 

Saadeh, A.M. (2001). Metabolic complications of organophosphate and carbamate poisoning. Trap. Doct. 31 149-52. 

Tang, J., Rose, R.L., Chambers, J.E. (2006). Metabolism of organophosphorus and carbamate pesticides. In Toxicology of Organophosphate and Carbamate Compounds (R.C. Gupta, ed.), Chapter 10, pp. 127-43. Elsevier, Amsterdam. 

Nomura, D.K., Fujioka, K., Issa, R.S., Ward, A.M., Cravatt, B.F., Casida, J.E. (2008). Dual roles of brain serine hydrolase KIAA1363 in ether lipid metabolism and organophosphate detoxification. Toxicol. Appl. Pharmacol. 228 42-8. 

---