Butyrylcholinesterase-catalysed hydrolysis of aspirin, a negatively charged ester, and aspirin-related neutral esters

Masson, Patrick; Froment, Marie Thérèse; Fortier, Pierre Louis; Visicchio, Jean Emmanuel; Bartels, Cynthia F.; Lockridge, Oksana

doi:10.1016/s0167-4838(98)00104-6

Cited by 65 publications

(31 citation statements)

References 51 publications

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“…2B), respectively, suggesting that these two enzymes represent the primary hydrolytic activity in liver microsomes toward each drug. Several other enzymes such as butyrylcholinesterase have been shown to hydrolyze aspirin (Masson et al, 1998). However, these enzymes have a K m value of millimolar level; therefore, HCE2 (K m ϭ 360 M; Fig.…”

Section: Discussionmentioning

confidence: 99%

Antiplatelet Agents Aspirin and Clopidogrel Are Hydrolyzed by Distinct Carboxylesterases, and Clopidogrel Is Transesterificated in the Presence of Ethyl Alcohol

Tang

Mukundan²,

Yang³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

227

183

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Aspirin (acetylsalicylic acid) and clopidogrel are two major antithrombogenic agents that are widely used for the treatment and prevention of cerebro-and cardiovascular conditions such as stroke. Combined use produces enhanced therapeutic effect. Aspirin and clopidogrel both are esters, and hydrolysis leads to decreased or inactivated therapeutic activity. The aim of the study was to determine whether aspirin and clopidogrel are hydrolyzed by the same enzyme(s), thus reciprocally prolonging the antithrombogenic activity. To test this possibility, microsomes from the liver and intestine were assayed for the hydrolysis of aspirin and clopidogrel. In contrary to the hypothesis, aspirin and clopidogrel were hydrolyzed in a tissue-differential manner. Liver microsomes hydrolyzed both drugs, whereas intestinal microsomes hydrolyzed aspirin only. Consistent with the tissue distribution of two carboxylesterases human carboxylesterase (HCE) 1 and HCE2, recombinant HCE1 hydrolyzed clopidogrel, whereas recombinant HCE2 hydrolyzed aspirin. In addition, hydrolysis of clopidogrel among liver samples was correlated well with the level of HCE1, and hydrolysis of aspirin with HCE2. Certain natural variants differed from the wild-type enzymes on the hydrolysis of aspirin or clopidogrel. In the presence of ethyl alcohol, clopidogrel is converted to ethyl clopidogrel. Carboxylesterases are important pharmacological determinants for drugs containing ester linkages and exhibit a large interindividual variation. The isoform-specific hydrolysis of aspirin and clopidogrel suggests that these two antithrombogenic agents may have pharmacokinetic interactions with different sets of ester drugs, and the altered hydrolysis by polymorphic mutants provides a molecular explanation to the interindividual variation.

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Section: Discussionmentioning

confidence: 99%

Antiplatelet Agents Aspirin and Clopidogrel Are Hydrolyzed by Distinct Carboxylesterases, and Clopidogrel Is Transesterificated in the Presence of Ethyl Alcohol

Tang

Mukundan²,

Yang³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

227

183

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“…Although the closely related enzyme acetylcholinesterase (AChE) is well described as the primary synaptic regulator of cholinergic transmission, a definitive physiological role for BChE has not yet been demonstrated (3). BChE is catalytically promiscuous and hydrolyzes not only acetylcholine (ACh), but also longer-chain choline esters (e.g., butyrylcholine, its preferred substrate, and succinylcholine) and a variety of non-choline esters, such as acetylsalicylic acid (aspirin) and cocaine (4,5). Moreover, BChE binds most environmentally occurring ChE inhibitors as well as man-made organophosphorous (OP) pesticides and nerve agents (NAs) (6,(7)(8)(9)(10).…”

mentioning

confidence: 99%

Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, protects rodents against nerve agents

Geyer

Kannan

Garnaud

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The concept of using cholinesterase bioscavengers for prophylaxis against organophosphorous nerve agents and pesticides has progressed from the bench to clinical trial. However, the supply of the native human proteins is either limited (e.g., plasma-derived butyrylcholinesterase and erythrocytic acetylcholinesterase) or nonexisting (synaptic acetylcholinesterase). Here we identify a unique form of recombinant human butyrylcholinesterase that mimics the native enzyme assembly into tetramers; this form provides extended effective pharmacokinetics that is significantly enhanced by polyethylene glycol conjugation. We further demonstrate that this enzyme (but not a G117H/E197Q organophosphorus acid anhydride hydrolase catalytic variant) can prevent morbidity and mortality associated with organophosphorous nerve agent and pesticide exposure of animal subjects of two model species.countermeasures | nonconventional warfare agents | organophosphorous pesticides | protein engineering | transgenic plants B utyrylcholinesterase (BChE) is the major cholinesterase (ChE) in the serum of humans (1, 2). Although the closely related enzyme acetylcholinesterase (AChE) is well described as the primary synaptic regulator of cholinergic transmission, a definitive physiological role for BChE has not yet been demonstrated (3). BChE is catalytically promiscuous and hydrolyzes not only acetylcholine (ACh), but also longer-chain choline esters (e.g., butyrylcholine, its preferred substrate, and succinylcholine) and a variety of non-choline esters, such as acetylsalicylic acid (aspirin) and cocaine (4, 5). Moreover, BChE binds most environmentally occurring ChE inhibitors as well as man-made organophosphorous (OP) pesticides and nerve agents (NAs) (6, 7-10).The systemic biodistribution and affinity for ChE inhibitors allow endogenous BChE to provide broad-spectrum protection against various toxicants by their sequestration before they reach cholinergic synapses. However, under realistic high-dose exposure scenarios, BChE serum levels are too low to afford adequate protection, resulting in persistent cholinergic excitation due to irreversible inhibition of AChE and subsequent accumulation of ACh. Sublethal manifestations of this state include unregulated exocrine secretion and gastrointestinal hypermotility. Death usually results from unregulated stimulation at neuromuscular junction leading to hemodynamic instability and tetanic contraction of the respiratory muscles (11,12).Current OP poisoning therapy consists of atropine for muscarinic ACh receptor blockade and diazepam for symptomatic management of convulsions (12). Additionally, oxime therapy with 2-pralidoxime (2-PAM) can effectively reactivate some but not all OP-AChE adducts (13)(14)(15). This standard therapeutic approach can reduce mortality, but insufficiently prevents the incapacitation associated with OP toxicity (12, 16).Prophylaxis by administration of exogenous ChEs has proven successful in reducing OP-associated morbidity and mortality, but requires the availability of rel...

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“…There have been some reports that the acetyl group of aspirin binds with the lysine residue of HSA and thus the acylation of HSA supports the hydrolyzing activity of human plasma (Morikawa et al, 1979;Yang et al, 2007;Liyasova et al, 2010). In addition to its activity with respect to albumin, aspirin has long been known to be a substrate for human plasma BChE (Hofstee, 1951;Morgan and Truitt, 1965;Morikawa et al, 1979;Valentino et al, 1981;Masson et al, 1998). In addition to BChE and albumin, it was recently reported that aspirin is hydrolyzed by plasma PON (Santanam and Parthasarathy, 2007;Jaichander et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…2). To explain the positive effects of calcium and magnesium on BChE, Valentino et al (1981) and Masson et al (1998) have suggested a facilitating approach, in which negatively charged substrates (i.e., aspirin) form a complex with divalent cations and thereby enter more easily the active center of the BChE, which has a negative charge. However, another divalent cation, zinc, had a negative effect on hydrolase activity (Fig.…”

Section: Discussionmentioning

confidence: 99%

Aspirin Hydrolysis in Human and Experimental Animal Plasma and the Effect of Metal Cations on Hydrolase Activities

Bahar

Imai

2013

Drug Metabolism and Disposition

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The hydrolyzing properties of plasma esterases for aspirin were investigated in human plasma and plasma from experimental animals. The observed rates of aspirin hydrolysis were in the following order: rabbit > human > monkey > rat > mouse > dog > minipig. In human, monkey, and dog plasma, aspirin was hydrolyzed by their major hydrolases, paraoxonase (PON), butyrylcholinesterase (BChE), and albumin. In rabbit, mouse, and rat plasma, carboxylesterase (CES) was determined to be the enzyme responsible for aspirin hydrolysis, and in mouse and rat plasma, especially the latter, hydrolase activity was increased by the addition of ethopropazine, a specific inhibitor of BChE. Interestingly, divalent cations affected the plasma activity by enhancing or inhibiting the hydrolase activity of plasma BChE. The addition of 2 mM calcium increased the hydrolysis of aspirin in human, monkey, and dog plasma by 2.7-, 1.9-, and 2.3-fold, respectively. Magnesium showed a similar but lesser effect. Increasing concentrations of calcium and magnesium resulted in a two-phase stimulatory effect on aspirin hydrolysis in human plasma. In contrast, the addition of zinc had an inhibitory effect on plasma BChE activity. It is postulated that calcium and magnesium bind to BChE and thereby change the conformation of the enzyme to a more appropriate position for aspirin hydrolysis.

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Butyrylcholinesterase-catalysed hydrolysis of aspirin, a negatively charged ester, and aspirin-related neutral esters

Cited by 65 publications

References 51 publications

Antiplatelet Agents Aspirin and Clopidogrel Are Hydrolyzed by Distinct Carboxylesterases, and Clopidogrel Is Transesterificated in the Presence of Ethyl Alcohol

Antiplatelet Agents Aspirin and Clopidogrel Are Hydrolyzed by Distinct Carboxylesterases, and Clopidogrel Is Transesterificated in the Presence of Ethyl Alcohol

Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, protects rodents against nerve agents

Aspirin Hydrolysis in Human and Experimental Animal Plasma and the Effect of Metal Cations on Hydrolase Activities

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