Aging cholinesterases

Wandhammer, M., De Koning, M., van Grol, M., et al., 2013. A step toward the reactivation of aged cholinesterases—crystal structure of ligands binding to aged human butyrylcholinesterase. Chem. Biol. Interact. 203, 19-23. 

Age/sex Plasma cholinesterase (mU per mL per minute) Erythrocyte cholinesterase (ApH/hour)"... 

In a case-control study of pesticide factory workers in Brazil exposed to methyl parathion and formulating solvents, the incidence of chromosomal aberrations in lymphocytes was investigated (De Cassia Stocco et al. 1982). Though dichlorodiphenyltrichloroethane (DDT) was coformulated with methyl parathion, blood DDT levels in the methyl parathion-examined workers and "nonexposed" workers were not significantly different. These workers were presumably exposed to methyl parathion via both inhalation and dermal routes however, a dose level was not reported. The exposed workers showed blood cholinesterase depressions between 50 and 75%. However, the baseline blood cholinesterase levels in nonexposed workers were not reported. No increases in the percentage of lymphocytes with chromosome breaks were found in 15 of these workers who were exposed to methyl parathion from 1 week to up to 7 years as compared with controls. The controls consisted of 13 men who had not been occupationally exposed to any chemical and were of comparable age and socioeconomic level. This study is limited because of concomitant exposure to formulating solvents, the recent history of exposure for the workers was not reported, the selection of the control group was not described adequately, and the sample size was limited. 

Often, absorption occurs by multiple routes in humans. Dean et al. (1984) reported deaths and toxic effects as well as lowered blood cholinesterase levels and excretion of urinary 4-nitrophenol in several children who were exposed by inhalation, oral, and possibly dermal routes after the spraying of methyl parathion in a house. In the same incident (Dean et al. 1984), absorption was indicated in adults who also excreted 4-nitrophenol in the urine, though at lower levels than some of the children, and in the absence of other evidence of methyl parathion exposure. In this study, the potential for age-related differences in absorption rates could not be assessed because exposure levels were not known and the children may have been more highly exposed than the adults. Health effects from multiple routes are discussed in detail in Section 3.2. 

Pharmacologically, carbofuran inhibits cholinesterase, resulting in stimulation of the central, parasympathetic, and somatic motor systems. Sensitive biochemical tests have been developed to measure cholinesterase inhibition in avian and mammalian brain and plasma samples and are useful in the forensic assessment of carbamate exposure in human and wildlife pesticide incidents (Bal-lantyne and Marrs Hunt and Hooper 1993). Acute toxic clinical effects resulting from carbofuran exposure in animals and humans appear to be completely reversible and have been successfully treated with atropine sulfate. However, treatment should occur as soon as possible after exposure because acute carbofuran toxicosis can be fatal younger age groups of various species are more susceptible than adults (Finlayson et al. 1979). Carbofuran labels indicate that application is forbidden to streams, lakes, or ponds. In addition, manufacturers have stated that carbofuran is poisonous if swallowed, inhaled, or absorbed through the skin. Users are cautioned not to breathe carbofuran dust, fumes, or spray mist and treated areas should be avoided for at least 2 days (Anonymous 1971). Three points are emphasized at this juncture. First, some carbofuran degradation... 

At 0.3 mg/kg BW, 1 nestling died after the second dose (age 6 days) and another after the fifth dose vs. no deaths in controls at day 19, brain cholinesterase activity was depressed 51% and plasma activity 49%. At 1.0 mg/kg BW, 1 died after the third dose at day 19, brain cholinesterase activity level was depressed 75% and plasma cholinesterase 25%. At 3.0 mg/kg BW, 9 of 11 tested nestlings died within 8 h of the first dose, another within 8 h of the second dose, and the last was killed by a predator after the second dose. The 2 nestlings that survived a single dose were moribund and their brain cholinesterase activity was depressed 85%... 

The enzymes used by these workers were cholinesterase, prepared from horse serum, and horse-liver esterase. Parallel experiments were carried out with twice crystallized ovalbumin, and with an aged, dialysed specimen of horse serum with negligible esterase activity. 

Because 2-PAM is unable to reverse cholinesterase inhibition once "aging" has started, 2-PAM should be administered as soon as possible after exposure. Atropine and 2-PAM synergistically alleviate the manifestations of cholinesterase inhibition when co-administered (Goldfrank et al. 

Sawitsky, etal., 10 have shown that the cholinesterase activity of corpuscles in 15 normal individuals varied through a range of 7.25 to 10.34 units per ml. and of the plasma from 1.5 to 5.0 units per ml., but that for a given individual the values were relatively constant. The relative constancy of intra-individual values and the variation between individuals have been confirmed by other investigators." Females show more variation than males, but otherwise there is no significant sex difference. Age appears not to be an important factor. A logical assumption is that the variation is a reflection of genetic differences. 

Gard, N.W. and Hooper, M.J. 1993, Age dependent changes in plasma and brain cholinesterase activities of Eastern Blue-birds and European Starlings. J. Wildlife Dis. 29 1-7. 

Methyl parathion itself is not a strong cholinesterase inhibitor, but one of its metabolites, methyl paraoxon, is an active inhibitor. Methyl paraoxon inactivates cholinesterase by phosphorylation of the active site of the enzyme to form the dimethylphosphoryl enzyme. Over the following 24-48 hours there is a process, called aging, of conversion to the monomethylphosphoryl enzyme. ... 

Aging is of clinical interest in the treatment of poisoning because cholinesterase reactivators such as pralidoxime (2-PAM, Protopam) chloride are ineffective after aging has occurred. Measurement of metabolites of methyl parathion, p ra-nitrophenol, and dimethylphosphate in the urine has been used to monitor exposure to workers. ... 

Walker LC, Rosen RE. Alzheimer therapeutics what after the cholinesterase inhibitors Age Ageing 2006 35 332-5. 

Atropine does not counter muscle weakness and respiratory failure. To overcome this, pralidoxime (P2AM), a cholinesterase reactivator, is used in many countries, in an initial dose of 30 mg/kg intravenously followed by 8 mg/kg/h until clinical recovery. Oximes have to be given before the irreversible aging of the enzyme-organophosphorus... 

If the poisoning is due to an organophosphate, prompt administration of pralidoxime chloride will result in dephosphorylation of cholinesterases in the periphery and a decrease in the degree of the blockade at the skeletal neuromuscular junction. Since pralidoxime is a quaternary amine, it will not enter the CNS and therefore cannot reactivate central cholinesterases. In addition, pralidoxime is effective only if there has been no aging of the phosphorylated enzyme. Pralidoxime has a greater effect at the skeletal neuromuscular junction than at autonomic effector sites. 

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