Cholinesterases genetic variants

M13. Micheli, A., A rare constellation of serum cholinesterase genetic variants. Enzyme 13, 305-310 (1972). 

Lockridge O and Masson P (2000). Pesticides and susceptible populations people with butyryl-cholinesterase genetic variants may be at risk. Neu-roToxicology, 21, 113-126. 

Li W-F, Costa LG, Furlong CE Serum paraoxonase status a major factor in determining resistance to organophosphates. J Toxicol Environ Health 40 337-346,1993 Lockridge O, Masson P Pesticides and susceptible populations people with hutyryl-cholinesterase genetic variants may he at risk. Neurotoxicology 21 113-126, 2000. 

Lehmann, H., and Liddell, J. (1969), Human cholinesterase genetic variants and their recognition. Br. J. Anaesth. 41,... 

Neuromuscular blockade produced by succinylcholine and mivacurium can be prolonged in patients with a genetically abnormal variant of plasma cholinesterase. The dibucaine number is a measure of the ability of a patient to metabolize succinylcholine and can be used to identify at-risk patients. Under standardized test conditions, dibucaine inhibits the normal enzyme by 80% and the abnormal enzyme by only 20%. Many genetic variants of plasma cholinesterase have been identified, although the dibucaine-related variants are the most important. Given the rarity of these genetic variants, plasma cholinesterase testing is not a routine clinical procedure. 

Among the anions, fluoride and sulfate had the strongest inhibitory effect, with bromide being the weakest (F9). The exceptional inhibitory power of fluoride ion (in a concentration of about 10 mol/liter) has been much studied, without real insight to the mode of action (C12, H26). It has been used for the differential inhibition of the human genetic variants (H12). The inhibition of human cholinesterase by fluoride differs from that of chloride in many respects (H15), not least in the effective concentration. Sodium chloride operates in the mole-per-llter concentration range, and its inhibition appears to be very similar in character to that of the human enzyme by sodium bromide (D12). 

Differentiation based on fluoride inhibition. None of the reported methods utilizing dibucaine as an inhibitor is capable of differentiating all the known cholinesterase variants. Therefore, fluoride ion is also commonly used to help distinguish the genetic variants. When... 

D15. Dietz, A. A., Rubinstein, H. M., and Lubrano, T., Colorimetric determination of serum cholinesterase and its genetic variants by the propionylthiocholine-dithiobis(ni-trobenzoic acid) procedure. Clin. Chem. 19, 1309-1313 (1973). 

N6. Neitlich, H. W., Increased plasma cholinesterase activity and succinylcholine resistance A genetic variant. J. Clin. Invest. 45, 380-387 (1966). 

Pharmacokinetics Succinylcholine is composed of two acetylcholine molecules linked end to end. Succinylcholine is metabolized by plasma cholinesterase (butyrylcholinesterase or pseudocholinesterase), which determines the amount of drug reaching the end plate. It has a duration of action of only a few minutes if given as a single dose. Blockade may be prolonged in patients with genetic variants of plasma cholinesterase that metabolize succinylcholine very slowly. Succinylcholine is not rapidly hydrolyzed by acetylcholinesterase. 

Lockridge. O. (1990). Genetic variants of human serum cholinesterase influence metabolism of the muscle relaxant succinylcholinc, Bharmarol. Ther. 47, 35-60. 

V, DISTRIBUTION PROFILES AND GENETIC VARIANTS OF HUMAN BLOOD CHOLINESTERASES... 

Carboxylesterases include cholinesterase (pseudocholinesterase), arylcarboxyesterases, liver microsomal carboxylesterases, and other unclassified liver carboxylesterases. Cholinesterase hydrolyzes oholihe-like esters (succinylcholine) and procaine as well as acetylsalicylic acid. Genetic variant forms of cholinesterase have beeh idehtified in human serum (e.g., succinylcholine toxicity when administered as ganglionic blocker for muscle relaxation). Meperidine is hydrolyzed only by liver microsomal carboxylesterases (Fig. 10.19). Diphenoxylate is hydrolyzed to its active metabolite, diphenoxylic acid, within 1 hour (Fig. 10.19). Presumably, the peripheral pharmacological action of diphenoxylate is attributed to zwitterionic diphenoxylic acid, which is readily eliminated in the urine. 

Lehmann H, Liddell J (1969) Human cholinesterase (pseudocholinesterase) genetic variants and their recognition. Br J Anaesthesiol 41 235-244. 

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. 

Harris, H., and M. Whittaker. 1962. The serum cholinesterase variants. A study of twenty-two families selected via the "intermediate" phenotype. Ann. Hum. Genet. 26 59-72. 

The pharmacologists and clinical chemists interest in succinylcholine arose from the belief that the hydrolysis, and therefore inactivation, of the drug was brought about by the action of cholinesterase, and that in cases of prolonged response, the patient had a deficiency of the enzyme. The investigation of this thesis led to the discovery of the genetically determined variants of cholinesterase, which are described in Section 2. 

There are reports that still other types of cholinesterase variants can be identified by electrophoretic studies. In most cases, it has not been determined whether these are genetically determined variants or acquired variants. Most of these variants have been detected by electrophoresis in a sieving gel such as starch or polyacrylamide. However, it must always be kept in mind that two new slow-migrating bands are detectable after performing two-dimensional electrophoresis on serum that has been stored (H6). The first band appears after storage for about 10 days at either 4°C... 

Van Ros and Druet (V2) reported the discovery of a slow-migrating cholinesterase variant, which they named Cg, in the sera of four African subjects. Although this may be a hereditary trait, its familial nature has not been demonstrated. These same authors also studied by two-dimensional electrophoresis two other Africans who each had a pair of additional slow bands which were called and C. Again, the possibility that these may be genetic in origin has not been demonstrated. None of these three bands is identical to those which were identified as the fetal band or storage bands by Harris et al. (H6). 

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