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

• DOI: 10.1124/dmd.32.5.505
• Publication Date: 2004-04-21T00:14:39Z
• Authors: Sonal P. Sanghani; Sara K. Quinney; Tyler B. Fredenburg; Wilhelmina I. Davis; Daryl J. Murry; William F. Bosron
• Keywords: Carboxylesterase; Thioester

Carboxylesterases metabolize ester, thioester, carbamate, and amide compounds to more soluble acid, alcohol, amine products. They belong a multigene family with about 50% sequence identity between classes. CES1A1 CES2 are the most studied human isoenzymes from class 1 2, respectively. In this study, we report cloning expression of new isoenzyme, CES3, that belongs 3. The purified recombinant CES3 protein has carboxylesterase activity. carbamate prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11; irinotecan) its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), potent topoisomerase I inhibitor. CYP3A4 oxidizes CPT-11 two major oxidative metabolites, 7-ethyl-10-[4-<i>N</i>-(5-aminopentanoic acid)-1-piperidino] (APC) 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC). investigate whether these NPC APC, can be metabolized SN-38 by carboxylesterases, CES1A1, CES2, CES3. We find CPT-11, all carboxylesterases SN-38. highest catalytic activity 0.012 min^-1 μM^-1 among three for hydrolysis CPT-11. was an equally good substrate in comparison efficiency 0.005 μM^-1. APC very poor isoenzymes, exhibiting 0.015 × 10^-3 CES2. Catalytic 20- 2000-fold less than relative &gt; &gt;&gt; substrates.