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

• Published in: The Journal of biological chemistry Vol. 288; no. 17; pp. 11940 - 11948
• Main Authors: Zhou, Gang, Marathe, Gopal K., Hartiala, Jaana, Hazen, Stanley L., Allayee, Hooman, Tang, W.H.Wilson, McIntyre, Thomas M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.04.2013; American Society for Biochemistry and Molecular Biology
• Subjects: 1-Alkyl-2-acetylglycerophosphocholine Esterase - blood; 1-Alkyl-2-acetylglycerophosphocholine Esterase - genetics; Aspirin; Aspirin - pharmacokinetics; Aspirin - pharmacology; Blood Platelets - enzymology; Butyrylcholinesterase - blood; Butyrylcholinesterase - genetics; Coronary Artery Disease - drug therapy; Coronary Artery Disease - enzymology; Coronary Artery Disease - genetics; Cyclooxygenase (COX) Pathway; Eicosanoid Biosynthesis; Eicosanoid Regulation; Eicosanoid-specific Genes; Enzymology; Genome-Wide Association Study; Humans; Hydrolysis; Microtubule-Associated Proteins - blood; Microtubule-Associated Proteins - genetics; Plasma - enzymology; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Aggregation Inhibitors - pharmacology; Platelets; Polymorphism, Single Nucleotide; Eicosanoid-specific Genes; Eicosanoid Biosynthesis; Aspirin; Platelets; Cyclooxygenase (COX) Pathway; Eicosanoid Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.427674

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. Background: Aspirin use is extensive, but its short half-life limits bioavailability. Results: Butyrylcholinesterase (BChE) and PAFAH1b2 hydrolyze aspirin in plasma. Aspirin hydrolysis in plasma varies by up to 12-fold from non-genetic modulation of BChE activity. Conclusion: Two enzymes hydrolyze aspirin in plasma, and their contribution varies among individuals. Significance: Aspirin hydrolysis in plasma is variable, affecting platelet inhibition by aspirin.