PT  - JOURNAL ARTICLE
AU  - Sanghani, Sonal P.
AU  - Quinney, Sara K.
AU  - Fredenburg, Tyler B.
AU  - Davis, Wilhelmina I.
AU  - Murry, Daryl J.
AU  - Bosron, William F.
TI  - HYDROLYSIS OF IRINOTECAN AND ITS OXIDATIVE METABOLITES, 7-ETHYL-10-[4-<em>N</em>-(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
AID  - 10.1124/dmd.32.5.505
DP  - 2004 May 01
TA  - Drug Metabolism and Disposition
PG  - 505--511
VI  - 32
IP  - 5
4099  - http://dmd.aspetjournals.org/content/32/5/505.short
4100  - http://dmd.aspetjournals.org/content/32/5/505.full
SO  - Drug Metab Dispos2004 May 01; 32
AB  - 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 μM-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 μM-1. APC was a very poor substrate for all three isoenzymes, exhibiting a catalytic activity of 0.015 × 10-3 min-1 μM-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. The American Society for Pharmacology and Experimental Therapeutics