Aspirin Hydrolysis in Plasma Is a Variable Function of Butyrylcholinesterase and Platelet-activating Factor Acetylhydrolase 1b2 (PAFAH1b2)

Zhou, Gang; Marathe, Gopal K.; Hartiala, Jaana; Hazen, Stanley L.; Allayee, Hooman; Tang, W.H. Wilson; McIntyre, Thomas M.

doi:10.1074/jbc.m112.427674

Cited by 36 publications

(21 citation statements)

References 43 publications

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“…However, there is evidence that hydrocortisone may also have pro-inflammatory properties. For example, hydrocortisone can interact with anti-inflammatory drugs such as aspirin hydrolysis where it mediates esterase activity (36). Furthermore, when normal subjects were injected with 300 mg of hydrocortisone, there was an increase in toll like inflammatory receptor 2, 5, 9, high mobility group box-1 and matrix metalloproteinase-9 expression occurred (37).…”

Section: Discussionmentioning

confidence: 99%

Urate crystals induce macrophage PAF‑AH secretion which is differentially regulated by TGFβ1 and hydrocortisone

Yagnik

Hills

2018

Mol Med Report

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The aim of the present study was to establish the role of platelet‑activating factor acetyl hydrolase (PAF‑AH) in the resolution phase of gout using an established in vitro mononuclear cell model. The effects of signalling pathway inhibitors on PAF‑AH secretion, as well as the effects of the common treatments hydrocortisone and colchicine, an antibody against the anti‑inflammatory cytokine transforming growth factor β1 (TGFβ1), and the transcriptional inhibitor actinomycin D, were also investigated. The effect of recombinant PAF‑AH on cytokine secretion by these cells was also determined. Human peripheral blood‑derived monocytes were isolated and differentiated into macrophages. Monocytes and macrophages were stimulated with monosodium monohydrate urate (MSU) crystals or lipopolysaccharide in the presence or absence of AEG3482 [a c‑Jun N‑terminal kinase (JNK) inhibitor], MG132 (a proteasome inhibitor), hydrocortisone or colchicine. Cultures were then analysed for PAF‑AH secretion using ELISA. A 6‑fold upregulation of PAF‑AH secretion was observed following macrophage exposure to MSU crystals for 24 h (29.3±6 vs. 5.4±0.3 ng/ml unstimulated; P<0.05). Following 72 h, PAF‑AH levels decreased significantly (11.1±1.8; P<0.01). Secretion was further enhanced following pre‑treatment with the JNK protein kinase inhibitor AEG3482 prior to MSU crystal stimulation (P<0.05) and was abrogated when cells were preincubated with actinomycin D or the proteasome inhibitor MG132 (50, 100 and 200 µM). The addition of recombinant PAF‑AH (2.5‑10 ng/ml) to MSU crystal‑stimulated immature monocyte cultures significantly decreased pro‑inflammatory interleukin (IL)‑1β (unstimulated 687±124 vs. stimulated 113±30 pg/ml) and IL‑6 secretion (unstimulated 590±50 vs. stimulated 182±19 pg/ml). Treatment of MSU crystal‑stimulated macrophages with hydrocortisone (2 µM) also significantly decreased PAF‑AH release (P<0.05). Neutralising anti‑TGFβ1 addition decreased PAF‑AH dose‑dependently with the highest inhibition observed at 1 µg/ml (P<0.05). The results implicated that PAF‑AH may have an anti‑inflammatory role in the resolution phase of gout.

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Section: Discussionmentioning

confidence: 99%

Urate crystals induce macrophage PAF‑AH secretion which is differentially regulated by TGFβ1 and hydrocortisone

Yagnik

Hills

2018

Mol Med Report

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“…However, there are certain populations in which higher aspirin doses may be required. 57 Aspirin undergoes hydrolysis in the plasma 63 as well as in erythrocytes 64 with significant interindividual variability. To identify genetic determinants of plasma hydrolytic activity, a genome-wide association study (GWAS) was performed that identified a genetic variant (rs6445035) in proximity to the butyrylcholinesterase ( BCHE ) gene at genome-wide level of significance, such that each additional copy of the minor allele was associated with a 1.2 nmol/mL/min reduction in aspirin hydrolytic activity but explained 3% of the overall variability in response.…”

Section: Antiplatelet Pharmacogenomicsmentioning

confidence: 99%

“…To identify genetic determinants of plasma hydrolytic activity, a genome-wide association study (GWAS) was performed that identified a genetic variant (rs6445035) in proximity to the butyrylcholinesterase ( BCHE ) gene at genome-wide level of significance, such that each additional copy of the minor allele was associated with a 1.2 nmol/mL/min reduction in aspirin hydrolytic activity but explained 3% of the overall variability in response. 63 Therefore, genetic variation at BCHE is unlikely to explain much of the observed variability in aspirin response.…”

Section: Antiplatelet Pharmacogenomicsmentioning

confidence: 99%

Personalized antiplatelet and anticoagulation therapy: applications and significance of pharmacogenomics

Beitelshees

Voora²,

Lewis

2015

PGPM

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In recent years, substantial effort has been made to better understand the influence of genetic factors on the efficacy and safety of numerous medications. These investigations suggest that the use of pharmacogenetic data to inform physician decision-making has great potential to enhance patient care by reducing on-treatment clinical events, adverse drug reactions, and health care-related costs. In fact, integration of such information into the clinical setting may be particularly applicable for antiplatelet and anticoagulation therapeutics, given the increasing body of evidence implicating genetic variation in variable drug response. In this review, we summarize currently available pharmacogenetic information for the most commonly used antiplatelet (ie, clopidogrel and aspirin) and anticoagulation (ie, warfarin) medications. Furthermore, we highlight the currently known role of genetic variability in response to next-generation antiplatelet (prasugrel and ticagrelor) and anticoagulant (dabigatran) agents. While compelling evidence suggests that genetic variants are important determinants of antiplatelet and anticoagulation therapy response, significant barriers to clinical implementation of pharmacogenetic testing exist and are described herein. In addition, we briefly discuss development of new diagnostic targets and therapeutic strategies as well as implications for enhanced patient care. In conclusion, pharmacogenetic testing can provide important information to assist clinicians with prescribing the most personalized and effective antiplatelet and anticoagulation therapy. However, several factors may limit its usefulness and should be considered.

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“…In humans, aspirin is rapidly absorbed after oral administration [50]. Once absorbed, it undergoes hydrolysis by several plasma esterases including butyrylcholinseterase, paraoxonase, albumin, and platelet-activating factor acetylhydrolase [48, 51]. Therefore, we focused on the AUC 0→2h as it would more precisely characterize the effect of alcohol on aspirin hydrolysis by intestinal CES2 since aspirin plasma concentrations at later time points could be affected by plasma esterase activity.…”

Section: Discussionmentioning

confidence: 99%

Effects of Alcohol on Human Carboxylesterase Drug Metabolism

Parker

Meibohm

et al. 2014

Clin Pharmacokinet

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Background and Objective Human carboxylesterase-1 (CES1) and human carboxylesterase-2 (CES2) play an important role in metabolizing many medications. Alcohol is a known inhibitor of these enzymes but the relative effect on CES1 and CES2 is unknown. The aim of this study is to determine the impact of alcohol on the metabolism of specific probes for CES1 (oseltamivir) and CES2 (aspirin). Methods The effect of alcohol on CES1- and CES2-mediated probe drug hydrolysis was determined in vitro using recombinant human carboxylesterase. To characterize the in vivo effects of alcohol, healthy volunteers received each probe drug alone and in combination with alcohol followed by blood sample collection and determination of oseltamivir, aspirin, and respective metabolite pharmacokinetics. Results Alcohol significantly inhibited oseltamivir hydrolysis by CES1 in vitro but did not affect aspirin metabolism by CES2. Alcohol increased the oseltamivir area under the plasma concentration-time curve (AUC) from 0-6 h by 27% (range 11-46%, p=0.011) and decreased the metabolite/oseltamivir AUC 0-6 h ratio by 34% (range 25-41%, p<0.001). Aspirin pharmacokinetics were not affected by alcohol. Conclusions Alcohol significantly inhibited the hydrolysis of oseltamivir by CES1 both in vitro and in humans, but did not affect the hydrolysis of aspirin to salicylic acid by CES2. These results suggest that alcohol's inhibition of CES1 could potentially result in clinically significant drug interactions with other CES1-substrate drugs, but it is unlikely to significantly affect CES2-substrate drug hydrolysis.

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Aspirin Hydrolysis in Plasma Is a Variable Function of Butyrylcholinesterase and Platelet-activating Factor Acetylhydrolase 1b2 (PAFAH1b2)

Cited by 36 publications

References 43 publications

Urate crystals induce macrophage PAF‑AH secretion which is differentially regulated by TGFβ1 and hydrocortisone

Urate crystals induce macrophage PAF‑AH secretion which is differentially regulated by TGFβ1 and hydrocortisone

Personalized antiplatelet and anticoagulation therapy: applications and significance of pharmacogenomics

Effects of Alcohol on Human Carboxylesterase Drug Metabolism

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