title: Examination of the carboxylesterase phenotype in human liver.
abstract: Carboxylesterases (CES) metabolize esters. Two CES isoforms are expressed in human liver (CES1 and CES2) and liver extracts are used in reaction phenotyping studies to discern interindividual metabolic variation. We tested the hypothesis that an individual's CES phenotype can be characterized by reporter substrates/probes that interrogate native CES1 and CES2 activities in liver and immunoblotting methods. We obtained 25 livers and found that CES1 is the main hydrolytic enzyme. Moreover, although CES1 protein levels were similar, we observed large interindividual variation in bioresmethrin hydrolysis rates (17-fold), a pyrethroid metabolized by CES1 but not CES2. Bioresmethrin hydrolysis rates did not correlate with CES1 protein levels. In contrast, procaine hydrolysis rates, a drug metabolized by CES2 but not CES1, were much less variant (3-fold). Using activity-based fluorophosphonate probes (FP-biotin), which covalently reacts with active serine hydrolases, CES1 protein was the most active enzyme in the livers. Finally, using bioorthogonal probes and click chemistry methodology, the half-life of CES 1 and 2 in cultured HepG2 cells was estimated at 96 h. The cause of the differential CES1 activities is unknown, but the underlying factors will be important to understand because several carboxylic acid ester drugs and environmental toxicants are metabolized by this enzyme.
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, United States. mross@cvm.msstate.edu
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Ross
authors.forename: Abdolsamad
authors.initials: A
authors.lastname: Borazjani
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.forename: J Allen
authors.initials: JA
authors.lastname: Crow
authors.forename: Shuqi
authors.initials: S
authors.lastname: Xie
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016718:Arachidonic Acid / Q000378:metabolism; D001711:Biotransformation; D015153:Blotting, Western; D043182:Carboxylesterase / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D005260:Female; D006801:Humans; D006868:Hydrolysis; D047468:Immunoprecipitation; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D016718:Arachidonic Acid; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; C517204:CES2 protein, human; D043182:Carboxylesterase