Liver enzymes cholinesterase

Solberg and co-workers have applied discriminate analysis of clinical laboratory tests combined with careful clinical and anatomic diagnoses of liver disease in order to determine which combinations of the many dozen liver diagnostic tests available are the bes t ( ). These authors found that the measurement of GPT, GMT, GOT, ALP and ceruloplasmin were the most useful enzymatic tests, when combined with other non-enzymatic tests such as the measurement of bilirubin, cholesterol, hepatitis-B associated Australian antigen, etc. Another group of highly useful enzymes, not discussed in this review, are those clotting factors and the enzyme cholinesterase which are synthesized by the liver cells. 

As we soon learned, tetrahydro-aminoaeridine (THA) is less effeetive in some respeets than physostigmine in reversing seopolamine induced decrements in NF% scores (Fig. 67) but surprisingly, does seem to shorten the duration of belladonnoid intoxication. This may reflect a greater affinity for the cholinesterase enzyme. THA s tendency to cause temporaiy liver enzyme abnormalities, however, persuad us to avoid its further use. 

M16. Molander, D. W., Graver, L. F., and Packs, G. T., Liver enzymes, serum glutamic oxalacetic transminase, cholinesterase and alkaline phosphatase in primary and metastatic hepatic neoplasia. Acta Unio Int. Cancrum 16, 1478-1481 (1960). 

The liver synthesizes cholinesterases, and therefore drugs hydrolysed by these enzymes, such as aspirin, procaine and succinylcholine, show reduced metabolism. Thus, liver damage and disease may have a number of effects on the disposition of a compound which may be due to ... 

Physostigmine is very sluggishly absorbed from the GI-tract. The drug gets hydrolyzed by the enzymes cholinesterases, and is also metabolized in the liver. It is excreted mostly in the urine as its metabolites and partly as unchanged drug. The drug happens to cross the placental barrier and only very small quantum are usually excreted in the breast-milk. However, the penetration into the CNS is comparatively veiy slow. 

There is a second type of cholinesterase called butyrylcholinesterase, pseudocholinesterase, or cholinesterase. This enzyme is present in some nonneural cells in the central and peripheral nervous systems as well as in plasma and serum, the liver, and other organs. Its physiologic function is not known, but is hypothesized to be the hydrolysis of esters ingested from plants (Lefkowitz et al. 1996). Plasma cholinesterases are also inhibited by organophosphate compounds through irreversible binding this binding can act as a detoxification mechanism as it affords some protection to acetylcholinesterase in the nervous system (Parkinson 1996 Taylor 1996). 

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. 

Some OP compounds induce delayed neurotoxic effects ("delayed neuropathy") after acute poisoning. This delayed neurotoxic action is independent of cholinesterase inhibition but related to phosphorylation of a specific esterasic enzyme in the nervous tissue, called "neurotoxic esterase" or "neuropathy target esterase" (NTE) (Johnson, 1982). NTE is present in the nervous tissue, liver lymphocytes, platelets, and other tissues, but its physiological function is unknown. There is a rather large inter-individual variation of lymphocyte and platelet NTE activity (Table 2). 

It will be shown below that D.F.P. is rapidly destroyed in vitro and in vivo.2 Therefore, the recovery of serum cholinesterase activity is not representative of a reversal of enzyme inhibition, but is indicative of synthesis of new enzyme proteins. Since the regeneration rate of serum cholinesterase in patients with liver damage is significantly depressed as contrasted with that in the normal patient, it is concluded that the ability of such patients to synthesize this particular enzyme protein is decreased. This constitutes evidence for the view that the fiver is a primary locus for the formation of serum cholinesterase. 

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. 

Disulfoton and its breakdown products can be measured in the blood, urine, feces, liver, kidney, or body fat of exposed people. In cases of occupational or accidental exposure to disulfoton, the breakdown products are often measured in the urine. The breakdown products are relatively specific for disulfoton and a few other similar organophosphate pesticides and can be detected in urine for up to one week after people were last exposed. Because disulfoton inhibits cholinesterase in blood and in blood cells, inhibition of this enzyme activity may also suggest exposure to disulfoton. Cholinesterase activity in blood and in blood cells may remain inhibited for as long as 1-2 weeks after the last exposure. Because other organophosphate pesticides also inhibit cholinesterase activity in blood and blood cells, this test is not specific for disulfoton. The measurement of cholinesterase in blood and blood cells and the amount of disulfoton breakdown products in the urine cannot always predict how much disulfoton you were exposed to. Your doctor can send samples of your blood or urine to special laboratories that perform these tests. Chapters 2 and 6 provide more information about medical tests. 

In contrast to acetylcholinesterase, cholinesterase (acylcholine acyl-hydrolase, butyrylcholinesterase, EC 3.1.1.8) exhibits relatively unspecific esterase activity toward choline esters, with abroad specificity relative to the size of the acyl group. The enzyme is synthesized in the liver and can be found in smooth muscle, adipocytes, and plasma. Its physiological role remains partly obscure, but there is evidence that it is present transiently in the embryonic nervous system, where it is replaced in later stages of development by acetylcholinesterase. It has, therefore, been suggested that cholinesterase functions as an embryonic acetylcholinesterase. 

Thioesters play a paramount biochemical role in the metabolism of fatty acids and lipids. Indeed, fatty acyl-coenzyme A thioesters are pivotal in fatty acid anabolism and catabolism, in protein acylation, and in the synthesis of triacylglycerols, phospholipids and cholesterol esters [145], It is in these reactions that the peculiar reactivity of thioesters is of such significance. Many hydrolases, and mainly mitochondrial thiolester hydrolases (EC 3.1.2), are able to cleave thioesters. In addition, cholinesterases and carboxylesterases show some activity, but this is not a constant property of these enzymes since, for example, carboxylesterases from human monocytes were found to be inactive toward some endogenous thioesters [35] [146], In contrast, allococaine benzoyl thioester was found to be a good substrate of pig liver esterase, human and mouse butyrylcholinesterase, and mouse acetylcholinesterase [147],... 

Most of the hemiesters 8.136 underwent no or little enzymatic degradation in human plasma, in agreement with the known inertness of hemiesters toward cholinesterase (see Chapt. 7). In contrast, very rapid hydrolysis was usually seen in pig and rat liver preparations, indicating the involvement of carboxylesterases. The only inert compound was the 3,3-dimethylglutarate hemiester of paracetamol (8.136, X = C(CH3)2CH2, Fig. 8.12). Data on the hydrolysis of such prodrugs by human hepatic enzymes will be welcome. 

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. 

The body contains two main classes of cholinesterase acetylcholinesterase (EC 3.1.1.7) and butyrylcholinesterase (EC 3.1.1.8).27 The former, sometimes referred to as true cholinesterase, Is mainly a tissue enzyme and Is found mainly In such tissues as the synapses of the cholinergic system It Is also found In other tissues, such as erythrocytes, where Its function Is uncertain. The latter, referred to as pseudocholinesterase, Is a soluble enzyme that is synthesized In the liver and circulates in the plasma-... 

Tacrine is a non-competitive, irreversible inhibitor of both acetyl and butyryl cholinesterase, with a greater potency for the latter enzyme. Based on the outcome of placebo-controlled, double-blind studies, tacrine was the first anticholinesterase to be licensed for the symptomatic treatment of AD in the United States. The main disadvantage of tacrine lies in its hepatotoxicity (approximately 50% of patients were found to develop elevated liver transaminases which reversed on discontinuation of the drug). Because of such side effects and limited efficacy, tacrine is no longer widely prescribed. 

Based on the above discussion it was thought that the trifluoro-methyl ketones would be more polarized and thus create a great electrophilicity on the carbonyl carbon which facilitates -OH attack by the serine residue. Yet there is no carbon-oxygen bond to be cleaved In the ketone moiety, and therefore the enzyme-trifluoromethyl ketone transition state complex does not undergo catalytic conversion. The above rationale seems reasonable as trifluoromethyl ketones were found to be extraordinary selective and potent inhibitors of cholinesterases (56) of JHE from T. ni (57) and of meperidine carboxylesterases from mouse and human livers (58). Since JH homologs are alpha-beta unsaturated esters, a sulfide bond was placed beta to the carbonyl in hopes that it would mimic the 2,3-olefln of JHs and yield more powerful inhibitors (54). This empirical approach was extremely successful since it resulted in compounds that were extremely potent inhibitors of JHEs from different species (51,54,59). 

The homochiral prostaglandin precursor (15,3fi)-330.1 was prepared [Scheme 4.330] by selective hydrolysis of the /weso-diacetate of cw-4-cyclopentene-13-diol 330 2 using pig liver esterase (PLE),617 whereas the enantiomer (1/ ,35)-330 3 was the product of electric eel cholinesterase (EECE) hydrolysis,618 Since enzyme-catalysed reactions are reversible, transesterification can also be used to prepare esters. In the case at hand, ciy-4-cydopentene-l,3-diol (330.4) was enan-tioselectively transesterified using pig pancreatic lipase (PPL) and trichloroethyl acetate.619 The trichloroethyl ester is used in order to influence the position of equilibrium since trichloroethanol is a better leaving group and weaker nucleophile than cyclopentenediol.620... 

There are different types of cholinesterases in the human body, which differ in their location in tissues, substrate affinity, and physiological function. The principal ones are acetylcholinesterase (AchE, EC 3.1.1.7), found in the nervous system and also present in the outer membrane of red blood cells, and plasma cholinesterases (EC 3.1.1.8, ChE), which are a group of enzymes present in plasma, liver, cerebrospinal fluid, and glial cells. Under normal physiological conditions, AChE performs the breakdown of acetylcholine (ACh), which is the chemical mediator... 

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