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Research ArticleArticle

Substrate Specificity of Carboxylesterase Isozymes and Their Contribution to Hydrolase Activity in Human Liver and Small Intestine

Teruko Imai, Megumi Taketani, Mayumi Shii, Masakiyo Hosokawa and Kan Chiba
Drug Metabolism and Disposition October 2006, 34 (10) 1734-1741; DOI: https://doi.org/10.1124/dmd.106.009381
Teruko Imai
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Megumi Taketani
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Mayumi Shii
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Masakiyo Hosokawa
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Kan Chiba
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Abstract

Hydrolase activity from human liver and small intestine microsomes was compared with that of recombinant human carboxylesterases, hCE-1 and hCE-2. Although both hCE-1 and hCE-2 are present in human liver, the dominant component was found to be hCE-1, whereas the hydrolase activity of the human small intestine was found to be predominantly hCE-2. hCE-2 has a limited ability to hydrolyze large acyl compound substrates. Interestingly, propranolol derivatives, good substrates for hCE-2, were easily hydrolyzed by substitution of the methyl group on the 2-position of the acyl moiety, but were barely hydrolyzed when the methyl group was substituted on the 3-position. These findings suggest that hCE-2 does not easily form acylated intermediates because of conformational interference in its active site. In contrast, hCE-1 could hydrolyze a variety of substrates. The hydrolytic activity of hCE-2 increased with increasing alcohol chain length in benzoic acid derivative substrates, whereas hCE-1 preferentially catalyzed the hydrolysis of substrates with short alcohol chains. Kinetic data showed that the determining factor for the rate of hydrolysis of p-aminobenzoic acid esters was Vmax for hCE-1 and Km for hCE-2. Furthermore, the addition of hydrophobic alcohols to the reaction mixture with p-aminobenzoic acid propyl ester induced high and low levels of transesterification by hCE-1 and hCE-2, respectively. When considering the substrate specificities of hCE-1, it is necessary to consider the transesterification ability of hCE-1, in addition to the binding structure of the substrate in the active site of the enzyme.

Footnotes

  • This work was supported in part by a Grant-in-Aid for Scientific Research (16590085) from the Japan Society for the Promotion of Science (T.I.)

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.009381.

  • ABBREVIATIONS: CES, carboxylesterase; CPT-11, camptothecin-11 (irinotecan); hCE-1, human carboxylesterase-1; hCE-2, human carboxylesterase-2; HPLC, high-performance liquid chromatography; PAGE, polyacrylamide gel electrophoresis.

    • Received January 19, 2006.
    • Accepted July 11, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (10)
Drug Metabolism and Disposition
Vol. 34, Issue 10
1 Oct 2006
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Research ArticleArticle

Substrate Specificity of Carboxylesterase Isozymes and Their Contribution to Hydrolase Activity in Human Liver and Small Intestine

Teruko Imai, Megumi Taketani, Mayumi Shii, Masakiyo Hosokawa and Kan Chiba
Drug Metabolism and Disposition October 1, 2006, 34 (10) 1734-1741; DOI: https://doi.org/10.1124/dmd.106.009381

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Research ArticleArticle

Substrate Specificity of Carboxylesterase Isozymes and Their Contribution to Hydrolase Activity in Human Liver and Small Intestine

Teruko Imai, Megumi Taketani, Mayumi Shii, Masakiyo Hosokawa and Kan Chiba
Drug Metabolism and Disposition October 1, 2006, 34 (10) 1734-1741; DOI: https://doi.org/10.1124/dmd.106.009381
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