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http://purl.uniprot.org/citations/15100172http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/15100172http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/15100172http://www.w3.org/2000/01/rdf-schema#comment"Carboxylesterases metabolize ester, thioester, carbamate, and amide compounds to more soluble acid, alcohol, and amine products. They belong to a multigene family with about 50% sequence identity between classes. CES1A1 and CES2 are the most studied human isoenzymes from class 1 and 2, respectively. In this study, we report the cloning and expression of a new human isoenzyme, CES3, that belongs to class 3. The purified recombinant CES3 protein has carboxylesterase activity. Carboxylesterases metabolize the carbamate prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11; irinotecan) to its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), a potent topoisomerase I inhibitor. CYP3A4 oxidizes CPT-11 to two major oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC) and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC). In this study, we investigate whether these oxidative metabolites, NPC and APC, can be metabolized to SN-38 by purified human carboxylesterases, CES1A1, CES2, and CES3. We find that CPT-11, APC, and NPC can all be metabolized by carboxylesterases to SN-38. CES2 has the highest catalytic activity of 0.012 min(-1) microM(-1) among the three carboxylesterases studied for hydrolysis of CPT-11. NPC was an equally good substrate of CES2 in comparison to CPT-11, with a catalytic efficiency of 0.005 min(-1) microM(-1). APC was a very poor substrate for all three isoenzymes, exhibiting a catalytic activity of 0.015 x 10(-3) min(-1) microM(-1) for CES2. Catalytic efficiency of CES3 for CPT-11 hydrolysis was 20-to 2000-fold less than that of CES1A1 and CES2. The relative activity of the three isoenzymes was CES2 > CES1A1 >> CES3, for all three substrates."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.org/dc/terms/identifier"doi:10.1124/dmd.32.5.505"xsd:string
http://purl.uniprot.org/citations/15100172http://purl.org/dc/terms/identifier"doi:10.1124/dmd.32.5.505"xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Bosron W.F."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Bosron W.F."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Murry D.J."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Murry D.J."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Davis W.I."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Davis W.I."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Sanghani S.P."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Sanghani S.P."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Fredenburg T.B."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Fredenburg T.B."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Quinney S.K."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/author"Quinney S.K."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/date"2004"xsd:gYear
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/date"2004"xsd:gYear
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/name"Drug Metab. Dispos."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/name"Drug Metab. Dispos."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/pages"505-511"xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/pages"505-511"xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/title"Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase isoenzyme, CES3."xsd:string
http://purl.uniprot.org/citations/15100172http://purl.uniprot.org/core/title"Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase isoenzyme, CES3."xsd:string
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