Biotransformations of 6',7'-dihydroxybergamottin and 6',7'-epoxybergamottin by the citrus-pathogenic fungi diminish cytochrome P450 3A4 inhibitory activity

Bioorg Med Chem Lett. 2012 Mar 15;22(6):2279-82. doi: 10.1016/j.bmcl.2012.01.081. Epub 2012 Jan 30.

Abstract

Penicillium digitatum, as well as five other citrus pathogenic species, (Penicillium ulaiense Link, Geotrichum citri Link, Botrytis cinerea P. Micheli ex Pers., Lasiodiplodia theobromae (Pat.) Griffon & Maubl., and Phomopsis citri (teleomorph Diaporthe citri)) were observed to convert 6',7'-epoxybergamottin (1) into 6',7'-dihydroxybergamottin (2), bergaptol (3), and an opened lactone ring metabolite 6,7-furano-5-(6',7'-dihydroxy geranyloxy)-2-hydroxy-hydrocoumaric acid (4). Metabolism of 2 by these fungi also proceeded to 4. The structure of 4 was established by high resolution mass spectrometry and (1)H and (13)C NMR techniques. The inhibitory activity of 4 towards human intestinal cytochrome P450 3A4 (CYP3A4) was greatly decreased (IC(50) >172.0 μM) compared to 2 (IC(50)=0.81 μM).

MeSH terms

  • Beverages
  • Biotransformation
  • Citrus paradisi / chemistry*
  • Citrus paradisi / microbiology
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors*
  • Food Technology
  • Fungi / metabolism*
  • Furocoumarins / metabolism*
  • Furocoumarins / toxicity
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry

Substances

  • Cytochrome P-450 CYP3A Inhibitors
  • Furocoumarins
  • epoxybergamottin
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • bergaptol
  • 6',7'-dihydroxybergamottin