Cholinesterases nonspecific cholinesterase

The inhibition of two cholinesterase activities in blood can also be used to confirm exposure to certain organophosphate ester compounds. Red blood cell acetylcholinesterase is the same cholinesterase found in the gray matter of the central nervous system and motor endplates of sympathetic ganglia. Synonyms for this enzyme include specific cholinesterase, true cholinesterase, and E-type cholinesterase. Plasma cholinesterase is a distinct enzyme found in intestinal mucosa, liver, plasma, and white matter of the central nervous system. Synonyms for this enzyme include nonspecific cholinesterase, pseudocholinesterase, butyrylcholinesterase, and S-type cholinesterase (Evans 1986). Nonspecific cholinesterase is thought to be a very poor indicator of neurotoxic effects. 

The phase-I metabolism of bambuterol is complex and involves both oxidation and hydrolysis. In human plasma, hydrolysis rapidly yields the monocarbamate metabolite, and then, slowly, terbutaline [164a], The reaction is catalyzed mainly by the nonspecific cholinesterase (EC 3.1.1.8) found in plasma [166]. In addition, cytochrome P450 catalyzed hydroxylation of an... 

In this drug class, only sucdnylcholine (succinyldicholine, suxamethonium, AJ is of clinical importance. Structurally, it can be described as a double ACh molecule. Like ACh, succinylcholine acts as agonist at endplate nicotinic cholino-ceptors, yet it produces muscle relaxation. Unlike ACh, it is not hydrolyzed by acetylcholinesterase. However, it is a substrate of nonspecific plasma cholinesterase (serum cholinesterase, p. 100). 

The effect of a standard dose of succinylcholine lasts only about 10 min. It is often given at the start of anesthesia to facilitate intubation of the patient. As expected, choUnesterase inhibitors are unable to counteract the effect of succinylcholine. In the few patients with a genetic deficiency in pseudocholinesterase (= nonspecific cholinesterase), the succinylcholine effect is significantly prolonged. 

This enzyme [EC 3.1.1.8] (also known as cholinesterase, pseudocholinesterase, acylcholine acylhydrolase, nonspecific cholinesterase, and benzoylcholinesterase) catalyzes the hydrolysis of an acylcholine to generate choline and a carboxylic acid anion. A variety of choline esters and a few other compounds can serve as substrates. 

Pseudo-ChE (also known as butyryl-, plasma, and nonspecific cholinesterase) has a widespread distribution, with enzyme especially abundant in the liver, where it is synthesized, and in the plasma. In spite of the abundance of pseudo-ChE, its physiological function has not been definitively identified. It does, however, play an important role in the metabolism of such clinically important compounds as succinylcholine, procaine, and numerous other esters. 

Cholinesterases (ChEs) are a ubiquitous group of enzymes that hydrolyze esters of choline. A well-known example is acetylcholinesterase (AChE, acetyl choline hydrolase, EC 3.1.1.7), the enzyme responsible for hydrolyzing the important neurotransmitter acetylcholine (ACh). Another ChE is butyrylcholi-nesterase (BuChE, acylcholine acylhydrolase, EC 3.1.1.8), also known as nonspecific cholinesterase. The preferred substrate for AChEs is ACh BuChEs prefer to hydrolyze esters like butyrylcholine and propionylcholine. Both AChE and BuChE are inhibited by some organophosphate (OP) and carbamate (CB) esters and also by other chemicals. 

Carbamyl choline is is a poor substrate for acetylcholinesterase and nonspecific cholinesterases (74). The nitrate ester (18, Table 2.1)... 

AChE is an essential confirmatory test for all fluids with elevated amniotic fluid AFP. Normal amniotic fluid contains a group of nonspecific cholinesterases referred to as pseudocholinesterase (PChE). Cerebrospinal fluid contains high concentrations of the neural enzyme AChE, and in cases of fetal open neural tube defects (and in about 80% of cases with defects of the abdominal wall), fluid leaks from the open lesion and allows AChE to enter the amniotic fluid. 

Use Biochemical research, determination of phosphorus in insecticides and poisons. (2) Pseudo or nonspecific cholinesterase prepared from horse serum. This esterase hydrolyzes other esters, as well as choline esters. It occurs in blood serum, the pancreas, and the liver. 

I Donepezil. DonepeziF is a piperidine cholinesterase inhibitor with specificity for inhibition of acetylcholinesterase as compared to butyrylcholinesterase. This specificity is claimed to result in fewer peripheral side effects (such as nausea, vomiting, and diarrhea) than with nonspecific cholinesterase inhibitors such as tacrine. ... 

Robertson RT, Yu BP, Liu HH, Kageyama GH (1991) Development of cholinesterase histochemical staining in cerebellar cortex transient expression of nonspecific cholinesterase in Purkinje cells of the nodulus and uvula. Exp. Neurol.. 114, 330-342. 

There are two main enzymes of interest. Acetylcholinesterase (AChE EC 3.1.1.7) has an affinity for the substrate acetylcholine and it is found in the erythrocytes and nervous tissue. The enzyme is sometimes referred to as true cholinesterase, and it exists in differing polymorphic forms (Skau 1985). Butyrylcholinesterase (BuChE, acylcholine acylhydrolase, EC 3.1.1.8)—also known as pseudocholinesterase or nonspecific cholinesterase— has affinities for the substrates butyrylcholine and/or pro-pionylcholine, which are dependent on the animal species (Myers 1953 Ecobichon and Comeau 1973 Scarsella et al. 1979 Unakami et al. 1987 Evans 1990 Matthew and Chapin 1990 Woodard et al. 1994). 

Butyrylcholinesterase occurs in the liver and at the motor endplates in muscle fibers and at synapses together with aeetylcholinesterase (Silver 1974). It is estimated that approximately 15% of total cholinesterase activity in the nervous system is due to the nonspecific cholinesterase activity in some of the white matter (Ecobichon and Joy 1982), and the synthesis of this nonspecific cholinesterase occurs in the liver. Several organophosphorus compounds can react and phosphorylate acetylcholinesterase carbamate ester compounds can carbamylate the enzyme, so both can inhibit the acetylcholinesterase. 

Ambulation was significantly increased 1 hour, but not 17 hours, after the last exposure. Biochemical changes in the brains following several additional exposures were reduced ribonucleic acid (RNA) content and increased nonspecific cholinesterase content. There was no histologic examination of brain tissue, so these findings could not be correlated with brain stmctural damage. 

Absorption of the quaternary carbamates from the conjunctiva, skin, and lungs is predictably poor, since their permanent charge renders them relatively insoluble in lipids. Thus, much larger doses are required for oral administration than for parenteral injection. Distribution into the central nervous system is negligible. Physostigmine, in contrast, is well absorbed from all sites and can be used topically in the eye (Table 7-4). It is distributed into the central nervous system and is more toxic than the more polar quaternary carbamates. The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well as by cholinesterase. However, the duration of their effect is determined chiefly by the stability of the inhibitor-enzyme complex (see Mechanism of Action, below), not by metabolism or excretion. 

As an explanation of the phosphoryltransferase activity of mammalian phosphatases, Morton (117) had earlier advanced the idea that phosphate ester hydrolysis catalyzed by the nonspecific phosphatases occurs in two catalytic steps similar to that shown by Wilson et al. (118) for cholinesterase. The first step is the formation of a phosphoryl enzyme with the splitting out of the alcohol group. The second step is the hydrolysis of the phosphoryl enzyme. 

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 wide use of cholinesterase inhibitors in various spheres of human activities and the risk of acute and chronic intoxications associated with this process prompted investigation of the role of acetylcholinesterase (AChE) and nonspecific esterases in the immunotropic effects of these chemicals. They irreversibly bind to AChE that normally catalyzes the hydrolysis of acetylcholine (ACh) at the... 

Pseudocholinesterase deficiency. The neuromuscular blocking action of suxamethonium is terminated by plasma pseudocholinesterase. True cholinesterase (acetylcholinesterase) hydrolyses acetylcholine released by nerve endings, whereas various tissues and plasma contain other nonspecific, hence pseudo, esterases. Affected individuals form so little plasma pseudocholinesterase that metabolism of suxamethonium is seriously reduced. The deficiency characteristically comes to light when a patient fails to breathe spontaneously after a surgical operation, and assisted ventilation may have to be undertaken for hours. Relatives of an affected individual—for this as for other inherited abnormalities carrying avoidable risk—should be sought out, checked to assess their own risk, and told of the result. The prevalence of pseudocholinesterase deficiency in the UK population is about 1 in 2500. 

Unlike the nonspecific effects and uncommon occurrence of direct mortality observed in wildlife exposed to chlorinated hydrocarbon pesticides, several studies have documented direct mortality from exposure to OP and carbamate insecticides. The method by which the OPs and carbamate insecticides affect wildlife is quite different from the method by which the chlorinated hydrocarbon insecticides effect wildlife. The OPs and carbamates inhibit cholinesterase, primarily acetylcholinesterase (AChE), which is an enzyme that functions in the breakdown of the neurotransmitter acetylcholine. Acetylcholine functions in the transmission of nerve impulses. Therefore, when AChE is inhibited by an OP or carbamate insecticide, it can no longer breakdown acetylcholine and there is continued transmission of nerve impulses that eventually leads to nerve and muscle exhaustion. The respiratory muscles are a critical muscle group that is affected, often leading to respiratory paralysis as the immediate cause of death. A major difference in the mode of action between OPs and carbamates is that the inhibition of AChE by OPs is, from a biological standpoint, irreversible, while the inhibition from exposure to carbamates is reversible in a biologically relevant time frame. There... 

Replacement of one or more of the hydrogen atoms of the ethylene bridge with alkyl groups produces marked changes in potency and activity. Acetyl /3-methylcholine (31) is equipotent to acetylcholine as a muscarinic agonist, but it has a much weaker nicotinic action (74). A factor in the observed potency of acetyl ]8-methylcholine is its slower rate of hydrolysis by acetylcholinesterase because of poor affinity of the compound for the enzyme s catalytic site (81) and its extremely high resistance to hydrolysis by nonspecific serum cholinesterases. 

---