Submitted to: Bioorganic and Medicinal Chemistry Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/20/2012
Publication Date: 1/31/2012
Citation: Myung, K., Manthey, J.A., Narciso, J.A. 2012. Biotransformations of 6',7'-dihydroxybergamottin and 6',7'-epoxybergamottin by the citrus-pathogenic fungi diminish cytochrome P450 3A4 inhibitory activity. Bioorganic and Medicinal Chemistry Letters. 22:2279-2282. Interpretive Summary: Citrus pathogenic fungi metabolize toxic compounds, termed furanocoumarins, in grapefruit into nontoxic products. The structure of a new metabolite is reported, as well as its inability to inhibit an enzyme that is needed for the grapefruit/drug interactions in humans.
Technical Abstract: Penicillium digitatum, as well as five other citrus pathogenic species, (P. ulaiense Link, Geotrichum citri Link, Botrytis cinerea P. Micheli ex Pers., Lasiodiplodia theobromae (Pat.)Griffon & Maubl. and Phomopsis citri (teleomorph Diaporthe citri)) was observed to convert 6',7'-epoxybergamottin (1) into 6',7'-dihydroxybergamottin (2), bergaptol (3), and an opened lactone ring metabolite (6',7'-dihydroxy)-2-carboxyl-1-hydroxy-hydrocoumarin (4). Metabolism of 2 by these fungi also proceeded to 4. The structure of 4 was established by high resolution mass spectrometry and 1H and 13C NMR techniques. The inhibitory activity of 4 towards human intestinal cytochrome P450 3A4 (CYP3A4) was greatly decreased (IC50 > 172.0 µM) compared to 2 (IC50 = 0.81 µM).