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Research ArticleArticle

Comparison of Metabolism of Sesamin and Episesamin by Drug-Metabolizing Enzymes in Human Liver

Kaori Yasuda, Shinichi Ikushiro, Shuto Wakayama, Toshimasa Itoh, Keiko Yamamoto, Masaki Kamakura, Eiji Munetsuna, Miho Ohta and Toshiyuki Sakaki
Drug Metabolism and Disposition October 2012, 40 (10) 1917-1926; DOI: https://doi.org/10.1124/dmd.112.045906
Kaori Yasuda
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (K.Y., S.I., M.K., E.M., T.S.); Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.W., T.I., K.Y.); and Development Nourishment Department, Soai University, Suminoe, Osaka, Japan (M.O.)
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Shinichi Ikushiro
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (K.Y., S.I., M.K., E.M., T.S.); Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.W., T.I., K.Y.); and Development Nourishment Department, Soai University, Suminoe, Osaka, Japan (M.O.)
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Shuto Wakayama
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (K.Y., S.I., M.K., E.M., T.S.); Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.W., T.I., K.Y.); and Development Nourishment Department, Soai University, Suminoe, Osaka, Japan (M.O.)
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Toshimasa Itoh
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (K.Y., S.I., M.K., E.M., T.S.); Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.W., T.I., K.Y.); and Development Nourishment Department, Soai University, Suminoe, Osaka, Japan (M.O.)
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Keiko Yamamoto
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (K.Y., S.I., M.K., E.M., T.S.); Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.W., T.I., K.Y.); and Development Nourishment Department, Soai University, Suminoe, Osaka, Japan (M.O.)
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Masaki Kamakura
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (K.Y., S.I., M.K., E.M., T.S.); Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.W., T.I., K.Y.); and Development Nourishment Department, Soai University, Suminoe, Osaka, Japan (M.O.)
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Eiji Munetsuna
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (K.Y., S.I., M.K., E.M., T.S.); Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.W., T.I., K.Y.); and Development Nourishment Department, Soai University, Suminoe, Osaka, Japan (M.O.)
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Miho Ohta
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (K.Y., S.I., M.K., E.M., T.S.); Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.W., T.I., K.Y.); and Development Nourishment Department, Soai University, Suminoe, Osaka, Japan (M.O.)
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Toshiyuki Sakaki
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (K.Y., S.I., M.K., E.M., T.S.); Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.W., T.I., K.Y.); and Development Nourishment Department, Soai University, Suminoe, Osaka, Japan (M.O.)
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Abstract

Sesamin and episesamin are two epimeric lignans that are found in refined sesame oil. Commercially available sesamin supplements contain both sesamin and episesamin at an approximate 1:1 ratio. Our previous study clarified the sequential metabolism of sesamin by cytochrome P450 (P450) and UDP-glucuronosyltransferase in human liver. In addition, we revealed that sesamin caused a mechanism-based inhibition (MBI) of CYP2C9, the P450 enzyme responsible for sesamin monocatecholization. In the present study, we compared the metabolism and the MBI of episesamin with those of sesamin. Episesamin was first metabolized to the two epimers of monocatechol, S- and R-monocatechols in human liver microsomes. The P450 enzymes responsible for S- and R-monocatechol formation were CYP2C9 and CYP1A2, respectively. The contribution of CYP2C9 was much larger than that of CYP1A2 in sesamin metabolism, whereas the contribution of CYP2C9 was almost equal to that of CYP1A2 in episesamin metabolism. Docking of episesamin to the active site of CYP1A2 explained the stereoselectivity in CYP1A2-dependent episesamin monocatecholization. Similar to sesamin, the episesamin S- and R-monocatechols were further metabolized to dicatechol, glucuronide, and methylate metabolites in human liver; however, the contribution of each reaction was significantly different between sesamin and episesamin. The liver microsomes from CYP2C19 ultra-rapid metabolizers showed a significant amount of episesamin dicatechol. In this study, we have revealed significantly different metabolism by P450, UDP-glucuronosyltransferase, and catechol-O-methyltransferase for sesamin and episesamin, resulting in different biological effects.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.112.045906.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    UGT
    UDP-glucuronosyltransferase
    HPLC
    high-performance liquid chromatography
    TFA
    trifluoroacetic acid
    DMSO
    dimethyl sulfoxide
    COMT
    catechol-O-methyltransferase
    SAM
    (S)-adenosylmethionine
    AZT
    3′-azido-3′-deoxythymidine
    MBI
    mechanism-based inhibition
    GlcUA
    glucuronic acid.

  • Received March 27, 2012.
  • Accepted June 29, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (10)
Drug Metabolism and Disposition
Vol. 40, Issue 10
1 Oct 2012
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Research ArticleArticle

METABOLISM OF SESAMIN AND EPISESAMIN IN HUMANS

Kaori Yasuda, Shinichi Ikushiro, Shuto Wakayama, Toshimasa Itoh, Keiko Yamamoto, Masaki Kamakura, Eiji Munetsuna, Miho Ohta and Toshiyuki Sakaki
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1917-1926; DOI: https://doi.org/10.1124/dmd.112.045906

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Research ArticleArticle

METABOLISM OF SESAMIN AND EPISESAMIN IN HUMANS

Kaori Yasuda, Shinichi Ikushiro, Shuto Wakayama, Toshimasa Itoh, Keiko Yamamoto, Masaki Kamakura, Eiji Munetsuna, Miho Ohta and Toshiyuki Sakaki
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1917-1926; DOI: https://doi.org/10.1124/dmd.112.045906
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