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Aspergillus niger metabolism of citrus furanocoumarin inhibitors of human cytochrome P450 3A4

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Abstract

Fungi metabolize polycyclic aromatic hydrocarbons by a number of detoxification processes, including the formation of sulfated and glycosidated conjugates. A class of aromatic compounds in grapefruit is the furanocoumarins (FCs), and their metabolism in humans is centrally involved in the “grapefruit/drug interactions.” Thus far, the metabolism by fungi of the major FCs in grapefruit, including 6′, 7′-epoxybergamottin (EB), 6′, 7′-dihydroxybergamottin (DHB), and bergamottin (BM), has received little attention. In this study, Aspergillus niger was observed to convert EB into DHB and a novel water-soluble metabolite (WSM). Bergaptol (BT) and BM were also metabolized by A. niger to the WSM, which was identified as BT-5-sulfate using mass spectrometry, UV spectroscopy, chemical hydrolysis, and 1H and 13C nuclear magnetic resonance spectroscopy. Similarly, the fungus had a capability of metabolizing xanthotoxol (XT), a structural isomer of BT, to a sulfated analog of BT-5-sulfate, presumably XT-8-sulfate. A possible enzyme-catalyzed pathway for the grapefruit FC metabolism involving the cleavage of the geranyl group and the addition of a sulfate group is proposed.

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Acknowledgments

We thank Ms. Veronica Cook and Mr. Christopher Ference for their technical assistance. We also thank Spectral Data Service (Champaign, IL) for NMR analysis. Mention of a trademark or proprietary product is for identification only and does not imply a guarantee or warranty of the product by the US Department of Agriculture.

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Correspondence to Kyung Myung.

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Myung, K., Manthey, J.A. & Narciso, J.A. Aspergillus niger metabolism of citrus furanocoumarin inhibitors of human cytochrome P450 3A4. Appl Microbiol Biotechnol 78, 343–349 (2008). https://doi.org/10.1007/s00253-007-1314-0

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Keywords

  • Aspergillus niger
  • Furanocoumarins
  • 6′, 7′-Epoxybergamottin
  • 6′, 7′-Dihydroxybergamottin
  • Bergamottin
  • Bergaptol
  • Xanthotoxol
  • Bergaptol-5-sulfate
  • Xanthotoxol-8-sulfate