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Research ArticleArticle

Differences between Human and Rat Intestinal and Hepatic Bisphenol A Glucuronidation and the Influence of Alamethicin on In Vitro Kinetic Measurements

Christopher S. Mazur, John F. Kenneke, Janet K. Hess-Wilson and John C. Lipscomb
Drug Metabolism and Disposition December 2010, 38 (12) 2232-2238; DOI: https://doi.org/10.1124/dmd.110.034819
Christopher S. Mazur
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John F. Kenneke
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Janet K. Hess-Wilson
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John C. Lipscomb
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Abstract

The extent to which membrane-disrupting agents, such as alamethicin, may alter cofactor transport and influence in vitro kinetic measurements of glucuronidation is a major concern regarding the characterization and extrapolation of inter- and intraspecies pharmacokinetics of bisphenol A (BPA). An additional concern is the omission of a BPA intestinal metabolism component in current pharmacokinetic models used to assess oral exposure. In this study, BPA glucuronidation in native hepatic microsomes from female rat and female human liver displayed higher Vmax values than that in males. In the presence of alamethicin, all hepatic Vmax values increased; however, this increase was disproportionately greater in males and gender differences were no longer observed. Female rats exhibited a much higher Km than all other species and genders; the addition of alamethicin had little influence on Km values for any of the test systems. The dissimilar Km measured for female rat suggests that different UDP-glucuronosyltransferase (UGT) enzyme(s) are involved in BPA glucuronidation. The presence of different UGTs in female rat was confirmed using Hill coefficients measured from diclofenac-mediated chemical inhibition assays within hepatic microsomes and purified human UGT2B7 and UGT2B15. Mixed-gender human intestinal microsomes showed little BPA glucuronidation reactivity compared with those from male rat intestine. Male rat intestinal microsomes in the presence of alamethicin exhibited a Vmax that was nearly 30-fold higher than that for mixed human microsomes. The species and gender metabolic differences we observed between rat and human liver and intestine provide key information for delineating BPA pharmacokinetics needed for human health risk assessment.

Footnotes

  • This article has been reviewed in accordance with the U.S. Environmental Protection Agency's peer and administrative review policies and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

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

    doi:10.1124/dmd.110.034819.

  • ABBREVIATIONS:

    BPA
    bisphenol A
    UGT
    UDP-glucuronosyltransferase
    UDPGA
    UDP-glucuronic acid
    ACN
    acetonitrile
    HPLC
    high-performance liquid chromatography
    MSP
    microsomal protein.

  • Received June 1, 2010.
  • Accepted August 23, 2010.
  • U.S. Government work not protected by U.S. copyright
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Drug Metabolism and Disposition: 38 (12)
Drug Metabolism and Disposition
Vol. 38, Issue 12
1 Dec 2010
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Research ArticleArticle

Differences between Human and Rat Intestinal and Hepatic Bisphenol A Glucuronidation and the Influence of Alamethicin on In Vitro Kinetic Measurements

Christopher S. Mazur, John F. Kenneke, Janet K. Hess-Wilson and John C. Lipscomb
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2232-2238; DOI: https://doi.org/10.1124/dmd.110.034819

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Research ArticleArticle

Differences between Human and Rat Intestinal and Hepatic Bisphenol A Glucuronidation and the Influence of Alamethicin on In Vitro Kinetic Measurements

Christopher S. Mazur, John F. Kenneke, Janet K. Hess-Wilson and John C. Lipscomb
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2232-2238; DOI: https://doi.org/10.1124/dmd.110.034819
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