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Research ArticleArticle

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

Sonal P. Sanghani, Sara K. Quinney, Tyler B. Fredenburg, Wilhelmina I. Davis, Daryl J. Murry and William F. Bosron
Drug Metabolism and Disposition May 2004, 32 (5) 505-511; DOI: https://doi.org/10.1124/dmd.32.5.505
Sonal P. Sanghani
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Sara K. Quinney
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Tyler B. Fredenburg
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Wilhelmina I. Davis
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Daryl J. Murry
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William F. Bosron
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Abstract

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.

Footnotes

  • ↵1 Abbreviations used are: CPT-11, irinotecan or 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin; CES, carboxylesterase; SN-38, 7-ethyl-10-hydroxycamptothecin; APC, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin; NPC, 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin; SN-38G (10-O-glucoronyl-SN-38; UGT, uridine diphosphate glucuronosyltransferase; PCR, polymerase chain reaction; PAGE, polyacrylamide gel electrophoresis; MALDI-TOF, matrix-assisted laser desorption/ionization-time of flight; kb, kilobase(s); nt, nucleotide(s); α-NA, α-naphthyl acetate.

  • ↵2 Carboxylesterase Nomenclature: Human carboxylesterases are named according to the phylogenetic alignment of genes from several species into four major classes (Satoh and Hosokawa, 1998). CES1A1 (also called hCE-1, GI: 16905523) belongs to class 1, CES2 belongs to class 2 (also called hCE-2, GI: 37622884), and CES3 belongs to class 3 (GI: 7019977).

  • Supported by National Institutes of Health Grants R21 CA93833 (W.F.B.) and T32 HL07182 (S.P.S.), Purdue Research Foundation (S.K.Q.), and Proteomics Core of the Indiana Genomics Initiative.

    • Received November 24, 2003.
    • Accepted February 4, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (5)
Drug Metabolism and Disposition
Vol. 32, Issue 5
1 May 2004
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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 …
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Research ArticleArticle

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

Sonal P. Sanghani, Sara K. Quinney, Tyler B. Fredenburg, Wilhelmina I. Davis, Daryl J. Murry and William F. Bosron
Drug Metabolism and Disposition May 1, 2004, 32 (5) 505-511; DOI: https://doi.org/10.1124/dmd.32.5.505

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Research ArticleArticle

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

Sonal P. Sanghani, Sara K. Quinney, Tyler B. Fredenburg, Wilhelmina I. Davis, Daryl J. Murry and William F. Bosron
Drug Metabolism and Disposition May 1, 2004, 32 (5) 505-511; DOI: https://doi.org/10.1124/dmd.32.5.505
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