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Research ArticleArticle

ABSORPTION/METABOLISM OF SULFORAPHANE AND QUERCETIN, AND REGULATION OF PHASE II ENZYMES, IN HUMAN JEJUNUM IN VIVO

Niclas Petri, Christer Tannergren, Birgit Holst, Fred A. Mellon, Yongping Bao, Geoff W. Plumb, Jim Bacon, Karen A. O'Leary, Paul A. Kroon, Lars Knutson, Patrik Forsell, Thomas Eriksson, Hans Lennernas and Gary Williamson
Drug Metabolism and Disposition June 2003, 31 (6) 805-813; DOI: https://doi.org/10.1124/dmd.31.6.805
Niclas Petri
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Christer Tannergren
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Birgit Holst
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Fred A. Mellon
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Yongping Bao
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Geoff W. Plumb
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Jim Bacon
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Karen A. O'Leary
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Paul A. Kroon
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Lars Knutson
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Patrik Forsell
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Thomas Eriksson
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Hans Lennernas
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Gary Williamson
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Abstract

For the first time the human intestinal effective permeability, estimated from the luminal disappearance and intestinal metabolism of phytochemicals, sulforaphane and quercetin-3,4′-glucoside, as well as the simultaneous changes in gene expression in vivo in enterocytes, has been studied in the human jejunum in vivo (Loc-I-Gut). Both compounds as components of an onion and broccoli extract could readily permeate the enterocytes in the perfused jejunal segment. At the physiologically relevant, dietary concentration tested, the average effective jejunal permeability (Peff) and percentage absorbed (± S.D.) were 18.7 ± 12.6 × 10-4 cm/s and 74 ± 29% for sulforaphane and 8.9 ± 7.1 × 10-4 cm/s and 60 ± 31% for quercetin-3,4′-diglucoside, respectively. Furthermore, a proportion of each compound was conjugated and excreted back into the lumen as sulforaphane-glutathione and quercetin-3′-glucuronide. The capacity of the isolated segment to deconjugate quercetin from quercetin-3,4′-diglucoside during the perfusion was much higher than the β-glucosidase activity of the preperfusion jejunal contents, indicating that the majority (79–100%) of the β-glucosidase capacity derives from the enterocytes in situ. Simultaneously, we determined short-term changes in gene expression in exfoliated enterocytes, which showed 2.0 ± 0.4-fold induction of glutathione transferase A1 (GSTA1) mRNA (p < 0.002) and 2.4 ± 1.2-fold induction of UDP-glucuronosyl transferase 1A1 (UGT1A1) mRNA (p < 0.02). The changes in gene expression were also seen in differentiated Caco-2 cells, where sulforaphane was responsible for induction of GSTA1 and quercetin for induction of UGT1A1. These results show that food components have the potential to modify drug metabolism in the human enterocyte in vivo very rapidly.

Footnotes

  • ↵ 1 Current address: Toxicology Unit, Section on Clinical Pharmacology, Imperial College, Hammersmith Campus, DuCane Road, London, W12 ONN, UK.

  • ↵ 2 Abbreviations used are: Peff, effective jejunal permeability; Q, flow rate; LC/MS, liquid chromatography/mass spectrometry; PEG; polyethylene glycol; NWF, net water flux; fabs, fraction absorbed; L, length; C, concentrations of the analyte; GSH, glutathione; l-Cys, l-cysteine; SIM, selected ion monitoring; HPLC, high performance liquid chromatography; EMEM, Eagle's minimal essential medium; RT-PCR, reverse transcription-polymerase chain reaction; Ct, threshold cycle; LPH, lactase phlorizin hydrolase; UGT, UDP-glucuronosyltransferase; GST, glutathione transferase.

  • Part of this work was supported by funding from the Biotechnology and Biological Science Research Council, UK.

    • Received November 1, 2002.
    • Accepted February 27, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (6)
Drug Metabolism and Disposition
Vol. 31, Issue 6
1 Jun 2003
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Research ArticleArticle

ABSORPTION/METABOLISM OF SULFORAPHANE AND QUERCETIN, AND REGULATION OF PHASE II ENZYMES, IN HUMAN JEJUNUM IN VIVO

Niclas Petri, Christer Tannergren, Birgit Holst, Fred A. Mellon, Yongping Bao, Geoff W. Plumb, Jim Bacon, Karen A. O'Leary, Paul A. Kroon, Lars Knutson, Patrik Forsell, Thomas Eriksson, Hans Lennernas and Gary Williamson
Drug Metabolism and Disposition June 1, 2003, 31 (6) 805-813; DOI: https://doi.org/10.1124/dmd.31.6.805

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Research ArticleArticle

ABSORPTION/METABOLISM OF SULFORAPHANE AND QUERCETIN, AND REGULATION OF PHASE II ENZYMES, IN HUMAN JEJUNUM IN VIVO

Niclas Petri, Christer Tannergren, Birgit Holst, Fred A. Mellon, Yongping Bao, Geoff W. Plumb, Jim Bacon, Karen A. O'Leary, Paul A. Kroon, Lars Knutson, Patrik Forsell, Thomas Eriksson, Hans Lennernas and Gary Williamson
Drug Metabolism and Disposition June 1, 2003, 31 (6) 805-813; DOI: https://doi.org/10.1124/dmd.31.6.805
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