Organophosphorus compounds metabolism

Chen HH, Sirianni SR, Huang CC. 1982. Sister chromatid exchanges in Chinese hamster cells treated with seventeen organophosphorus compounds in the presence of a metabolic activation system. Environ Mutagen 4 621-624. 

Miyamoto J, Sato Y, Kadota T, et al. 1963a. Studies on the mode of action of organophosphorus compounds. Part I. Metabolic fate of P32 labeled sumithion and methylparathion in guinea pig and white rat. Agric Biol Chem 27 381-389. 

Famphur and other organophosphorus compounds are metabolized and excreted with greater efficiency by mammals than the target pests before these compounds can bind to and ultimately inhibit the cholinesterase enzyme (Randell and Bradley 1980). Mice, for example, degrade famphur rapidly. Less than 1 h after an intraperitoneal injection of 1 mg famphur/kg BW, only 8.34% of... 

The Role of Phosphonates in Living Systems, Hilderbrand, R.L., Ed., CRC Press, Boca Raton, FL, 1983 — Contributed chapters survey the role of naturally occurring organophosphorus compounds (containing a C-P bond) in biological systems and the use of a wide variety of organophosphorus compounds for the regulation of metabolism and the treatment of disease. 

Thus, although organophosphorus compounds like fenitrothion may be metabolized in aquatic organisms through oxidative desulfuration, side chain oxidation, hydrolytic cleavage of P-O-arryl linkage, as well as O-demethylation, the turn-over rate apparently is much lower than in mammals. 

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],... 

Methods for Determining Biomarkers of Exposure and Effect. Section 2.6.1 reported on biomarkers used to identify or quantify exposure to diazinon. Some methods for the detection of the parent compound in biological samples were described above. The parent chemical is quickly metabolized so the determination of metabolites can also serve as biomarkers of exposure. The most specific biomarkers will be those metabolites related to 2-isopropyl-6-methyl-4-hydroxypyrimidine. A method for this compound and 2-(r-hydroxy-l -methyl)-ethyl-6-methyl-4-hydroxypyrimidine in dog urine has been described by Lawrence and Iverson (1975) with reported sensitivities in the sub-ppm range. Other metabolites most commonly detected are 0,0-diethylphosphate and 0,0-diethylphosphorothioate, although these compounds are not specific for diazinon as they also arise from other diethylphosphates and phosphorothioates (Drevenkar et al. 1993 Kudzin et al. 1991 Mount 1984 Reid and Watts 1981 Vasilic et al. 1993). Another less specific marker of exposure is erythrocyte acetyl cholinesterase, an enzyme inhibited by insecticidal organophosphorus compounds (see Chapter 2). Methods for the diazinon-specific hydroxypyrimidines should be updated and validated for human samples. Rapid, simple, and specific methods should be sought to make assays readily available to the clinician. Studies that relate the exposure concentration of diazinon to the concentrations of these specific biomarkers in blood or urine would provide a basis for the interpretation of such biomarker data. 

Other important enzyme inhibitors of this type are the organophosphorus compounds. Thus, after metabolism to the oxygen analogues, the insecticides parathion and malathion (chap. 4, Fig. 25) (Fig. 5.12) form complexes with the enzyme acetylcholinesterase as described in more detail in chapter 7. 

The onset of symptoms depends on the particular organophosphorus compound, but is usually relatively rapid, occurring within a few minutes to a few hours, and the symptoms may last for several days. This depends on the metabolism and distribution of the particular compound and factors such as lipophilicity. Some of the organophosphorus insecticides such as malathion, for example (chap. 5, Fig. 12), are metabolized in mammals mainly by hydrolysis to polar metabolites, which are readily excreted, whereas in the insect, oxidative metabolism occurs, which produces the cholinesterase inhibitor. Metabolic differences between the target and nontarget species are exploited to maximize the selective toxicity. Consequently, malathion has a low toxicity to mammals such as the rat in which the LD50 is about 10 g kg-1. 

Inhibition of the cholinesterase enzymes depends on blockade of the active site of the enzyme, specifically the site that binds the ester portion of acetylcholine (Fig. 7.48). The organophosphorus compound is thus a pseudosubstrate. However, in the case of some compounds such as the phosphorothionates (parathion and malathion, for example), metabolism is necessary to produce the inhibitor. 

Although a particular organophosphorus compound may be rapidly metabolized and therefore not accumulate in the animal, chronic dosing may cause a cumulative toxic effect because of the slow rate of reversal of the inhibition. Thus, the rate of regeneration may be slow... 

This group of compounds is used as pesticides and nerve gases. The structure and therefore metabolism and potency varies. However, they all act in a similar manner. There are two toxic effects, cholinesterase inhibition and delayed neuropathy, but all OPs do not necessarily cause both. The cholinesterase inhibition results from the similarity between the organophosphorus compound and acetylcholine. The organophosphorus compound therefore acts as a pseudosubstrate but blocks the enzyme, in some cases, permanently. This is because the... 

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