title: Aspirin hydrolysis in plasma is a variable function of butyrylcholinesterase and platelet-activating factor acetylhydrolase 1b2 (PAFAH1b2).
abstract: Aspirin is rapidly hydrolyzed within erythrocytes by a heterodimer of PAFAH1b2/PAFAH1b3 but also in plasma by an unidentified activity. Hydrolysis in both compartments was variable, with a 12-fold variation in plasma among 2226 Cleveland Clinic GeneBank patients. Platelet inhibition by aspirin was suppressed in plasma that rapidly hydrolyzed aspirin. Plasma aspirin hydrolysis was significantly higher in patients with coronary artery disease compared with control subjects (16.5 ± 4.4 versus 15.1 ± 3.7 nmol/ml/min; p = 3.4 × 10(-8)). A genome-wide association study of 2054 GeneBank subjects identified a single locus immediately adjacent to the BCHE (butyrylcholinesterase) gene associated with plasma aspirin hydrolytic activity (lead SNP, rs6445035; p = 9.1 × 10(-17)). However, its penetrance was low, and plasma from an individual with an inactivating mutation in BCHE still effectively hydrolyzed aspirin. A second aspirin hydrolase was identified in plasma, the purification of which showed it to be homomeric PAFAH1b2. This is distinct from the erythrocyte PAFAH1b2/PAFAH1b3 heterodimer. Inhibitors showed that both butyrylcholinesterase (BChE) and PAFAH1b2 contribute to aspirin hydrolysis in plasma, with variation primarily reflecting non-genetic variation of BChE activity. Therefore, aspirin is hydrolyzed in plasma by two enzymes, BChE and a new extracellular form of platelet-activating factor acetylhydrolase, PAFAH1b2. Hydrolytic effectiveness varies widely primarily from non-genetic variation of BChE activity that affects aspirin bioavailability in blood and the ability of aspirin to inhibit platelet aggregation.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhou
authors.forename: Gopal K
authors.initials: GK
authors.lastname: Marathe
authors.forename: Jaana
authors.initials: J
authors.lastname: Hartiala
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Thomas M
authors.initials: TM
authors.lastname: McIntyre
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000097:blood* / Q000235:genetics; D001241:Aspirin / Q000493:pharmacokinetics* / Q000494:pharmacology; D001792:Blood Platelets / Q000201:enzymology*; D002091:Butyrylcholinesterase / Q000097:blood* / Q000235:genetics; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D006868:Hydrolysis; D008869:Microtubule-Associated Proteins / Q000097:blood* / Q000235:genetics; D010949:Plasma / Q000201:enzymology*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide
chemical_list: D008869:Microtubule-Associated Proteins; D010975:Platelet Aggregation Inhibitors; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C523923:PAFAH1B2 protein, human; D002091:Butyrylcholinesterase; D001241:Aspirin