Cholinesterases, distribution

Krishna, G. V. R. Simha, S. S. (1980). A study of the nerve arrangement and cholinesterase distribution in Oochoristica sigmoides and Raillietina tetragona (Cestoda). Journal of Animal Morphology Physiology, 27 10—13. 

Friede RL, Fleming LM (1964) A comparison of cholinesterase distribution in the cerebellum of several species. J. Neurochem., 11, 1-7. 

The results from using the Student s f-test for a distributional analysis are presented in Table 4. These results indicate the probability of a given worker in the listed scenario exceeding the NOEL of the toxicity endpoint. The probability of exceeding the LOEL and of thus experiencing a depression of plasma cholinesterase activity is not given (except for chronic exposure scenarios in the "100 ug/kg bw/day" column). Hence, even these probabilities may be considered to be conservative and not fully representative of the probability of a worker actually experiencing a toxic effect. 

Cholinesterases are widely distributed throughout the body in both neuronal and non-neuronal tissues 195... 

Cholinesterases are widely distributed throughout the body in both neuronal and non-neuronal tissues. Based largely on substrate specificity, the cholinesterases are subdivided into the acetylcholinesterases (AChEs) (EC... 

C. H. Walker, H. M. Thompson, Phylogenetic Distribution of Cholinesterases and Related Esterases , Chem. Agric. 1991, 2, 1-17. 

It is well established that acetylcholine can be catabolized by both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) these are also known as "true" and "pseudo" cholinesterase, respectively. Such enzymes may be differentiated by their specificity for different choline esters and by their susceptibility to different antagonists. They also differ in their anatomical distribution, with AChE being associated with nervous tissue while BChE is largely found in non-nervous tissue. In the brain there does not seem to be a good correlation between the distribution of cholinergic terminals and the presence of AChE, choline acetyltransferase having been found to be a better marker of such terminals. An assessment of cholinesterase activity can be made by examining red blood cells, which contain only AChE, and plasma. 

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. 

Mechanism of Action A benzimidazole carbamate anthelmintic that degrades parasite cytoplasmic microtubules, irreversibly blocks cholinesterase secretion, glucose uptake in helminth and larvae (depletes glycogen, decreases ATP production, depletes energy). Vermicidal. Therapeutic Effect Immobilizes and kills worms. Pharmacokinetics Poorly and variably absorbed from GI tract. Widely distributed, cyst fluid and including cerebrospinal fluid (CSF). Protein binding 70%. Extensively metabolized in liver. Primarily excreted in urine and bile. Not removed by hemodialysis. Half-life 8-12 hr. 

Intolerance. Here, a patient shows a qualitatively normal response to the drug, but at an abnormally low dose. This may simply be a resp9nse at the extreme of the normal range of variation. The Gaussian distribution of response to a drug includes individuals who are unusually sensitive as well as those who are resistant. On the other hand, the response to some drugs shows two or more genetically determined populations, e.g. the response to suxamethonium in normal persons and in those with abnormal variants of cholinesterase. 

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. 

Tomokuni K, Hasegawa T, Hirai Y, et al. 1985. The tissue distribution of diazinon and the inhibition of blood cholinesterase activities in rats and mice receiving a single intraperitoneal dose of diazinon. Toxicology 37(l-2) 91-98. 

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. 

Reiner, E., V. Simeon-Rudolf, and M. Skrinjaric-Spoljar. 1995. Catalytic properties and distribution profiles of paraoxonase and cholinesterase phenotypes in human sera. Toxicol Lett 82/83, 447, 1995. 

Choline esters are poorly absorbed and poorly distributed into the central nervous system because they are hydrophilic. Although all are hydrolyzed in the gastrointestinal tract (and less active by the oral route), they differ markedly in their susceptibility to hydrolysis by cholinesterase in the body. Acetylcholine is very rapidly hydrolyzed (see Chapter 6 Introduction to Autonomic Pharmacology) large amounts must be infused intravenously to achieve concentrations high enough to produce detectable effects. A large intravenous bolus injection has a brief effect, typically... 

Kalow, W. and Staron, N. On distribution and inheritance of atypical forms of human serum cholinesterase, as indicated by dibucaine numbers. Can J Biochem Physiol 1957, 35 1305-1320. 

In the clinic, esmolol s distribution half-life is 2 min and its elimination half-life is 9 min. Esmolol hydrochloride is rapidly metabolized by hydrolysis of the ester linkage, chiefly by esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase [22]. Its volume of distribution is 3.4 L kg-1, and its total clearance is 285 mL kg-1 min-1, "... which is greater than cardiac output thus the metabolism ofesmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flout [22]. As expected from such a "... high rate of blood-based metabolism, less than 2% of the drug is excreted unchanged in the wind [22]. Within 24 h after infusion, approximately... 

Table 9.13 Number and class distribution of insect glutathione S-transferases (GSTs), cytochrome P450 monooxygenases (P450s), and carboxyl/cholinesterases (CCEs) from Drosophila melanogaster, Anopheles gambiae, and Apis mellifera...

Holmstedt, B. (1971). Distribution and determination of cholinesterases in mammals. Bull WHO 44 99-107. 

Koelle, G.B. (1963). Cytological distributions and physiological functions of cholinesterases. In Handbuch der Experimentellen Pharmakologie XV, Cholinesterases and Anticholinesterase Agents (E.D. Koelle, ed.), pp. 187-298. Springer-Verlag, Berlin. 

Echothiophate iodide is a long-lasting cholinesterase inhibitor of the irreversible type, as is isofluorphate. Unlike the latter, however, it is a quaternary salt, and when applied locally, its distribution in tissues is limited, which can be very de.sirablc. It is used as a long-acting anticholinesterase agent in the treatment of glaucoma. 

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