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Research ArticleArticle

Mouse Liver and Kidney Carboxylesterase (M-LK) Rapidly Hydrolyzes Antitumor Prodrug Irinotecan and the N-Terminal Three Quarter Sequence Determines Substrate Selectivity

Mingxing Xie, Dongfang Yang, Micheal Wu, Bob Xue and Bingfang Yan
Drug Metabolism and Disposition January 2003, 31 (1) 21-27; DOI: https://doi.org/10.1124/dmd.31.1.21
Mingxing Xie
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Dongfang Yang
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Micheal Wu
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Bob Xue
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Bingfang Yan
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Abstract

Antitumor prodrug irinotecan is used for a variety of malignancies such as colorectal cancer. It is hydrolyzed to the metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), which exerts its antineoplastic effect. Several human and rodent carboxylesterases are shown to hydrolyze irinotecan, but the overall activity varies from enzyme to enzyme. This report describes a novel mouse liver and kidney carboxylesterase (M-LK) that is highly active toward this prodrug. Northern analyses demonstrated that M-LK was abundantly expressed in the liver and kidney and slightly in the intestine and lung. Lysates from M-LK transfected cells exhibited a markedly higher activity on irinotecan hydrolysis than lysates from the cells transfected with mouse triacylglycerol hydrolase (TGH) (6.9 versus 1.3 pmol/mg/min). Based on the immunostaining intensity with purified rat hydrolase A, M-LK had a specific activity of 173 pmol/mg/min, which ranked it as one of the most efficient esterases known to hydrolyze irinotecan. A chimeric carboxylesterase and its wild-type enzyme (e.g., M-LKn and M-LK), sharing three quarters of the entire sequence from the N-terminus, exhibited the same substrate preference toward irinotecan and two other substrates, suggesting that the N-terminal sequence determines substrate selectivity. M-LK transfected cells manifested more severe cytotoxicity than TGH transfected cells upon being exposed to irinotecan. Topoisomerase I inhibitors such as irinotecan represent a promising class of anticancer drugs. Identification of M-LK as an efficient carboxylesterase to activate irinotecan provides additional sequence information to locate residues involved in irinotecan hydrolysis and thus facilitates the design of new analogs.

Footnotes

  • This work was partially supported by a Grant ES07965 from the National Institute of Environmental Health Sciences and a New Investigator Award from the American Association of Colleges of Pharmacy.

  • Abbreviations used are::
    Irinotecan
    7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11)
    HCE
    human carboxylesterase
    rCE
    rabbit carboxylesterase
    M-LK
    mouse liver and kidney carboxylesterase
    TGH
    triacylglycerol hydrolase
    HPLC
    high performance liquid chromatography
    LDH
    lactate dehydrogenase
    HS
    anti-hydrolase S antibody
    4PP
    4-piperidino-piperidine
    SN-38
    7-ethyl-10-hydroxycamptothecin
    • Received August 7, 2002.
    • Accepted September 24, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (1)
Drug Metabolism and Disposition
Vol. 31, Issue 1
1 Jan 2003
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Research ArticleArticle

Mouse Liver and Kidney Carboxylesterase (M-LK) Rapidly Hydrolyzes Antitumor Prodrug Irinotecan and the N-Terminal Three Quarter Sequence Determines Substrate Selectivity

Mingxing Xie, Dongfang Yang, Micheal Wu, Bob Xue and Bingfang Yan
Drug Metabolism and Disposition January 1, 2003, 31 (1) 21-27; DOI: https://doi.org/10.1124/dmd.31.1.21

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Research ArticleArticle

Mouse Liver and Kidney Carboxylesterase (M-LK) Rapidly Hydrolyzes Antitumor Prodrug Irinotecan and the N-Terminal Three Quarter Sequence Determines Substrate Selectivity

Mingxing Xie, Dongfang Yang, Micheal Wu, Bob Xue and Bingfang Yan
Drug Metabolism and Disposition January 1, 2003, 31 (1) 21-27; DOI: https://doi.org/10.1124/dmd.31.1.21
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