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Research ArticleArticle

Characterization of Hepatic and Intestinal Glucuronidation of Magnolol: Application of the Relative Activity Factor Approach to Decipher the Contributions of Multiple UDP-Glucuronosyltransferase Isoforms

Liangliang Zhu, Guangbo Ge, Hongbo Zhang, Huixin Liu, Guiyuan He, Sicheng Liang, Yanyan Zhang, Zhongze Fang, Peipei Dong, Moshe Finel and Ling Yang
Drug Metabolism and Disposition March 2012, 40 (3) 529-538; DOI: https://doi.org/10.1124/dmd.111.042192
Liangliang Zhu
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Guangbo Ge
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Hongbo Zhang
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Huixin Liu
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Guiyuan He
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Sicheng Liang
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Yanyan Zhang
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Zhongze Fang
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Peipei Dong
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Moshe Finel
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Ling Yang
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Abstract

Magnolol is a food additive that is often found in mints and gums. Human exposure to this compound can reach a high dose; thus, characterization of magnolol disposition in humans is very important. Previous studies indicated that magnolol can undergo extensive glucuronidation in humans in vivo. In this study, in vitro assays were used to characterize the glucuronidation pathway in human liver and intestine. Assays with recombinant human UDP-glucuronosyltransferase enzymes (UGTs) revealed that multiple UGT isoforms were involved in magnolol glucuronidation, including UGT1A1, -1A3, -1A7, -1A8, -1A9, -1A10, and -2B7. Magnolol glucuronidation by human liver microsomes (HLM), human intestine microsomes (HIM), and most recombinant UGTs exhibited strong substrate inhibition kinetics. The degree of substrate inhibition was relatively low in the case of UGT1A10, whereas the reaction catalyzed by UGT1A9 followed biphasic kinetics. Chemical inhibition studies and the relative activity factor (RAF) approach were used to identify the individual UGTs that played important roles in magnolol glucuronidation in HLM and HIM. The results indicate that UGT2B7 is mainly responsible for the reaction in HLM, whereas UGT2B7 and UGT1A10 are significant contributors in HIM. In summary, the current study clarifies the glucuronidation pathway of magnolol and demonstrates that the RAF approach can be used as an efficient method for deciphering the roles of individual UGTs in a given glucuronidation pathway in the native tissue that is catalyzed by multiple isoforms with variable and atypical kinetics.

Footnotes

  • This work was supported by the National Natural Science Foundation of China [Grants 30973590, 81001473]; the National Key Technology Research and Development Program of China [Grant 2009BADB9B02]; the State Key Development Program of Basic Research of China [Grant 2009CB522808]; the National High Technology Research and Development Program of China [Grant 2009AA02Z205]; the Knowledge Innovation Program of the Chinese Academy of Sciences [Grant KSCX2-YW-G-050]; and the Sigrid Juselius Foundation, Finland.

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

    http://dx.doi.org/10.1124/dmd.111.042192.

  • ABBREVIATIONS:

    UGT
    UDP-glucuronosyltransferase
    UDPGA
    uridine diphosphate glucuronic acid
    RAF
    relative activity factor
    AS-3201
    (R)-(−)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-4-spiro-3′-pyrrolidine-1,2′,3,5′-tetrone
    HPLC
    high-performance liquid chromatography
    HLM
    human liver microsomes
    AZT
    3′-azido-3′-deoxy-thymidine
    HIM
    human intestine microsomes
    UFLC
    ultrafast liquid chromatography
    DAD
    diode-array detector
    MS
    mass spectrometry
    ESI
    electrospray ionization
    LC
    liquid chromatography
    SPE
    solid-phase extraction.

  • Received August 4, 2011.
  • Accepted December 16, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

MAGNOLOL GLUCURONIDATION IN HLM AND HIM

Liangliang Zhu, Guangbo Ge, Hongbo Zhang, Huixin Liu, Guiyuan He, Sicheng Liang, Yanyan Zhang, Zhongze Fang, Peipei Dong, Moshe Finel and Ling Yang
Drug Metabolism and Disposition March 1, 2012, 40 (3) 529-538; DOI: https://doi.org/10.1124/dmd.111.042192

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Research ArticleArticle

MAGNOLOL GLUCURONIDATION IN HLM AND HIM

Liangliang Zhu, Guangbo Ge, Hongbo Zhang, Huixin Liu, Guiyuan He, Sicheng Liang, Yanyan Zhang, Zhongze Fang, Peipei Dong, Moshe Finel and Ling Yang
Drug Metabolism and Disposition March 1, 2012, 40 (3) 529-538; DOI: https://doi.org/10.1124/dmd.111.042192
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