Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cocaine was stable (93.6 +/- 5.0 (SD)% remaining after 120 minutes) when incubated in plasma from six patients with histories of succinylcholine sensitivity and low dibucaine numbers (phenotype A), but was rapidly hydrolyzed (40.6 +/- 6.6% remaining after 120 minutes) when incubated in plasma obtained from normal subjects (phenotype U). Intermediate decay (69.4 +/- 9.0% remaining) occurred in three heterozygous offspring of the succinylcholine-sensitive patients. Since serum cholinesterase has recently been implicated in the human metabolism of cocaine, patients who are homozygous for the atypical enzyme may be at greater risk for a toxic reaction when administered this drug. We recommend caution in using cocaine for topical anesthesia in patients with histories of succinylcholine sensitivity or low dibucaine numbers.
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PMID:Cocaine and succinylcholine sensitivity: a new caution. 57 61

To test our hypotheses that the hemodynamic response to cocaine may be altered during pregnancy, cocaine (0.33 mg/kg/min) was infused intravenously to chronically catheterized pregnant and nonpregnant female rats. Cardiac output and regional blood flow were measured, and cocaine concentrations in plasma and tissues, as well as plasma cholinesterase activity were determined. Results were compared between pregnant and nonpregnant groups. Cocaine produced a significant decrease in heart rate, accompanied by a fall in cardiac output, and decreased cerebral, myocardial, and placental blood flow in pregnant rats. The plasma cocaine concentration in pregnant animals was lower than that of nonpregnant ones, but tissue concentrations were similar in both groups. These results indicate that pregnancy enhances cardiovascular responses to subtoxic doses of cocaine. There was little placental transfer of cocaine with a fetal to maternal plasma concentration ratio of 0.28.
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PMID:Pregnancy alters the hemodynamic responses to cocaine in the rat. 134 Apr 39

We measured the blood levels of cocaine and its three major metabolites, benzoylecgonine, ecgonine methyl ester, and norcocaine, in three groups of male pigs weighing about 26 kg (25.75 +/- 0.25 kg) to determine the effects of inhibition of plasma cholinesterase and hepatic microsomal enzyme activity on cocaine metabolism. In addition, systemic elimination half-life, volume of distribution, and clearance of cocaine were calculated for the three groups. Group 1 pigs (n = 4) were pretreated with normal saline solution, group 2 pigs (n = 4) were pretreated with tetraisopropyl pyrophosphoramide, a specific plasma cholinesterase inhibitor, and group 3 pigs (n = 4) were pretreated with cimetidine, a hepatic microsomal enzyme inhibitor, all administered intramuscularly. Pigs were anesthetized with intravenous sodium thiopental; a carotid arterial cannula and an external jugular catheter were then inserted for the administration of cocaine and for blood sampling. Forty-five minutes later, when pigs were again completely awake, cocaine 3 mg/kg was given intravenously. Arterial blood samples were collected for the analysis of cocaine and cocaine metabolite levels just before and at 5, 10, 15, 30, 45, 60, 120, 180, and 1440 minutes after the administration of cocaine. Cocaine and cocaine metabolite blood levels were analyzed with high-pressure liquid chromatography methods and plasma cholinesterase activity was measured with a colorimetric method. The blood levels of cocaine and cocaine metabolites were significantly different among the three groups (p less than 0.05, analysis of variance). Statistically significant differences in half-life, volume of distribution and clearance were also seen among the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of inhibition of plasma cholinesterase and hepatic microsomal enzyme activity on cocaine, benzoylecgonine, ecgonine methyl ester, and norcocaine blood levels in pigs. 150 Aug 30

The behaviors of the enantiomers of cocaine (benzoylecgonine methyl ester) and related compounds with butyrylcholinesterase (BChE; EC 3.1.1.8) were investigated spectrophotometrically at 235 nm. The unnatural enantiomer, (+)-cocaine, was hydrolyzed by BChE (extinction coefficient 6.7 L.mmol-1.cm-1) at about half the rate of benzoylcholine, but over 2000 times faster than naturally occurring (-)-cocaine. This rapid hydrolysis of (+)-cocaine may account, in part, for its pharmacological inactivity. (+)-Norcocaine, (+)-benzoylecgonine, (-)-psi-cocaine and tropacocaine were also substrates for BChE. Hydrolysis of (+)-cocaine was sensitive to several standard inhibitors of BChE, including those of competitive, carbamate and organophosphorus classes. Although (-)-cocaine was a poor substrate for debenzoylation, it was a fairly good competitive inhibitor (Ki approximately 10 microM) of the hydrolysis of other substrates. The cocaine metabolites (-)-norcocaine, (-)-benzoylecgonine and (-)-ecgonine methyl ester inhibited BChE with Ki values of 15, 76 and 1300 microM, respectively. (+)-psi-Cocaine had Ki = 3 microM, p-Nitro and p-fluoro derivatives of cocaine and analogs with phenyl and p-fluorophenyl groups in place of the benzoyl ester linkage (WIN 35,065-2 and WIN 35,428) inhibited BChE comparably to (-)-cocaine itself. Both cocaine enantiomers were weak inhibitors of acetylcholinesterase (AChE; EC 3.1.1.7) from human erythrocytes with similar Ki values (160-170 microM). Although it is unlikely that the inhibition of BChE is an important factor in the subjective effects of cocaine, it may have implications for the toxicity of cocaine to the fetus, since BChE appears in the development of the central nervous system before AChE, and has been suggested to function as an embryonic acetylcholinesterase.
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PMID:Activities of the enantiomers of cocaine and some related compounds as substrates and inhibitors of plasma butyrylcholinesterase. 200 99

Cocaine is a potent hepatotoxin in laboratory mice, although the cocaine-induced hepatotoxicity (CIH) is due to the action of a metabolite of cocaine. Cocaine can be hydrolyzed by serum cholinesterase (ChE) to inactive products, or be oxidized by hepatic cytochrome P-450 and FAD-containing monooxygenase (FADM). The oxidative pathway is thought to be responsible for production of the hepatotoxic metabolite of cocaine, presumably norcocaine nitroxide. Female mice are much more resistant to CIH than males of the same strain. We have found that immature male mice are as resistant as females to the development of CIH. Males did not show any CIH until the onset of puberty (30 days of age), indicating that the development of CIH in males was under hormonal control. To determine if the major cocaine-metabolizing enzymes were responsible for the regulation of CIH, we measured the activities of ChE, cocaine N-demethylation (CND) and FADM as a function of sex in C57BL/6Ibg and DBA/2Ibg mice 20-21, 30 +/- 1 and 65 +/- 5 days of age. There was a significant sex difference in ChE activity (females higher than males) but no effect of age. Cocaine N-demethylation increased in both males and females with age, but there was no consistent sex difference. Activity of FADM declined in males as a function of age, but remained constant in females. The lack of a consistent correlation between enzyme activities and sex-, strain-, and age-dependent differences in susceptibility to CIH, do not support a regulatory role for ChE, CND or FADM in mediating the hepatotoxic response.
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PMID:Strain, sex and developmental profiles of cocaine metabolizing enzymes in mice. 226 58

Effects of cocaine on the isotonic contractions of isolated vas deferens of intact and reserpinized guinea pigs to acetylcholine were examined. Both cocaine-induced increase in sensitivity to acetylcholine and cocaine-induced increase in maximum response of Ca2+-contraction was attenuated remarkably by reserpine. However, cocaine-induced increases in acetylcholine- and K+-contractions in Ca2+-free Tyrode solution were not prevented by reserpine. Acetylcholine-contraction, but not K+-contraction, in the preparation exposed for 5 min to Ca2+-free Tyrode solution were inhibited by reserpine. Cocaine did not inhibit the cholinesterase activity of vas deferens of guinea pig. These results suggested that presynaptic mechanisms of cocaine-induced supersensitivity are excluded and that inhibitory effect of reserpine on cocaine-induced supersensitivity might be due to the inhibition of cocaine-induced increase in calcium-influx into smooth muscle cells of vas deferens.
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PMID:Pharmacological studies on supersensitization. VIII. Dissociation of induction of supersensitivity from presynaptic action of cocaine on isolated vas deferens of guinea pig. 716 7

Cocaine was the first drug to be used as a local anaesthetic. It was introduced into medicine in 1884 by Koller. Other drugs soon followed, for example, ethyl chloride spray, tropocaine, eugenol (oil of cloves) and Nupercaine. A wide range of uses for local anaesthetics soon developed and the term 'regional anaesthesia' was first used by Cushing in 1901 to describe pain relief by nerve blockade. Local anaesthetic drugs are water soluble salts of lipid soluble alkaloids. Each molecule is composed of an aromatic portion, intermediate chain and an amide portion. The portions are joined by either amide or ester linkages. Ester-linked drugs are hydrolysed in the plasma by plasma cholinesterase and their half-life varies from one to eight minutes. Amide-linked drugs are degraded by oxidative dealkylation in the liver. The half-life of these drugs varies from 1.5 to more than three hours. The addition of a vasoconstrictor, such as adrenaline, will prolong the duration of action of both the amide- and ester-linked drugs. Degradation of the amide-linked drugs depends on factors such as hepatic blood flow and liver conditions, such as cirrhosis, and congestive cardiac failure. Anaphylactic reactions are more common with ester-linked drugs than amide-linked drugs. The drugs are usually available for injection as hydrochlorides in a salt solution with small amounts of fungicides or preservatives added to give stability.
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PMID:Local anaesthesia in the operating theatre. 799 96

Concomitant i.v. use of cocaine and heroin ("speedballing") is prevalent among drug-abusing populations. Heroin is rapidly metabolized by sequential deacetylation of two separate ester bonds to yield 6-monoacetylmorphine and morphine. Hydrolysis of heroin to 6-monoacetylmorphine is catalyzed by pseudocholinesterase. The pathway for hydrolysis of 6-monoacetylmorphine to morphine in vivo has yet to be established. Pseudocholinesterase and two human liver carboxylesterases [human liver carboxylesterase form 1 (hCE-1) and human liver carboxylesterase form 2 (hCE-2)] catalyze the rapid hydrolysis of ester linkages in cocaine. This investigation examined the relative catalytic efficiencies of hCE-1, hCE-2 and pseudocholinesterase for heroin metabolism and compared them with cocaine hydrolysis. Enzymatic formation of 6-monoacetylmorphine and morphine was determined by reverse-phase high-performance liquid chromatography. All three enzymes rapidly catalyzed hydrolysis of heroin to 6-monoacetylmorphine (hCE-1 kcat = 439 min-1, hCE-2 kcat = 2186 min-1 and pseudocholinesterase kcat = 13 min-1). The catalytic efficiency, under first-order conditions, for hCE-2-catalyzed formation of 6-monoacetylmorphine (314 min-1 mM-1) was much greater than that for either hCE-1 or pseudocholinesterase (69 and 4 min-1 mM-1, respectively). Similarly, the catalytic efficiency for hydrolysis of 6-monoacetylmorphine to morphine by hCE-2 (22 min-1 mM-1) was substantially greater than that for hCE-1 (0.024 min-1 mM-1). Cocaine competitively inhibited hCE-1-, hCE-2- and pseudocholinesterase-catalyzed hydrolysis of heroin to 6-monoacetylmorphine (Ki = 530, 460 and 130 microM, respectively) and 6-monoacetylmorphine hydrolysis to morphine (Ki = 710, 220 and 830 microM, respectively). These data demonstrate that metabolism of cocaine and heroin in humans is mediated by common metabolic pathways. The role of hepatic hCE-2 is particularly important for the hydrolysis of heroin to 6-monoacetylmorphine and of 6-monoacetylmorphine to morphine.
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PMID:Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases. 893 Jan 75

The most common complications of cocaine ingestion are on the cardiovascular and central nervous systems and produce chest pain and generalized seizures. In humans, decreased levels of butyrylcholinesterase (BChE) (EC 3.1.1.8) have been associated with sustained effects of cocaine and life-threatening complications. Administration of purified human BChE has previously been demonstrated to protect against cocaine-associated cardiovascular toxicity in rats. A shift in the metabolism of cocaine as well as enhanced metabolism may be the underlying mechanism of the enzyme. Therefore, levels of the parent drug and four metabolites were determined in rat plasma after i.p. administration of a lethal cocaine dose, followed by i.v. administration of BChE. Plasma and brain concentrations of cocaine were lowered by 80% after BChE administration. Furthermore, the metabolic profile of cocaine in the plasma was altered. The concentration of ecgonine methylester was doubled although the concentration of ecgonine, a secondary metabolite of cocaine, was reduced. The level of benzoylecgonine was reduced by one-half while norcocaine was absent. Cocaine-associated effects upon the central nervous system were also shown to be reduced by administration of BChE to conscious rats. Furthermore, our studies in the cat have also shown that purified BChE shifts the metabolic profile of cocaine (1 mg/kg) to the pharmacologically inactive products ecgonine methylester and ecgonine. Pretreatment with BChE (0.27, 1.0, and 10.0 mg/kg) ameliorated the hypertensive effects of cocaine (1 mg/kg) by reducing the duration and the extent of BP elevation by 66%. Administration of the enzyme, 1 min after cessation of cocaine infusion, resulted in an immediate attenuation in the cocaine-induced broadening of the QRS complex. These results suggest that BChE could be an effective and rapid therapy for the treatment of life-threatening cocaine-induced cardiovascular effects in human while clearing the total body burden of cocaine.
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PMID:Therapeutic use of butyrylcholinesterase for cocaine intoxication. 926 11

In humans, the plasma enzyme butyrylcholinesterase, BChE (EC 3.1.1.8), mediates the in vivo plasma hydrolysis of cocaine to the pharmacologically inactive metabolite ecgonine methyl ester, EME. This enzyme has been purified from human plasma to investigate the potential as a treatment for cocaine intoxication. Cocaine (2.1 micrograms mL-1) was incubated in plasma with a BChE concentration in the normal range (3.02 micrograms mL-1) and in plasma with enhanced BChE concentrations of 9.14, 20.8 and 37.8 micrograms mL-1, respectively for time periods up to 120 min. Cocaine and the hydrolytic products, ecgonine methyl ester and ecgonine, were quantified simultaneously by gas chromatography-mass spectrometry (GC-MS). The enhancement of plasma BChE concentration resulted in a dramatic increase in the rate of hydrolysis of cocaine. There was a stoichimetric conversion of cocaine to the inactive hydrolysis product, ecgonine methyl ester. Accordingly, the half-life of cocaine in plasma decreased significantly with enhanced BChE concentration. At plasma BChE concentrations of 3.02, 9.14, 20.8 and 37.8 micrograms mL-1, half-life values of 116, 35.8, 21.4 and 9.0 min, respectively were observed. The marked reduction in cocaine half-life provides evidence supporting the potential therapeutic use of BChE for the treatment of cocaine intoxication.
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PMID:The influence of plasma butyrylcholinesterase concentration on the in vitro hydrolysis of cocaine in human plasma. 967 83


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