Aspergillus niger metabolism of citrus furanocoumarin inhibitors of human cytochrome P450 3A4.
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 (1)H and (13)C 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.
Myung
Kyung
K
Citrus and Subtropical Products Laboratory, Agricultural Research Service, US Department of Agriculture, 600 Ave. S, N.W., Winter Haven, FL, 33881, USA. Kyung.Myung@ars.usda.gov
Manthey
John A
JA
Narciso
Jan A
JA
D001234:Aspergillus niger / Q000378:metabolism*; D032083:Citrus paradisi / Q000737:chemistry; D011564:Furocoumarins / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013057:Spectrum Analysis
D011564:Furocoumarins; C475527:epoxybergamottin; C021768:xanthotoxol; C068337:bergamottin; C080771:bergaptol; C104774:6',7'-dihydroxybergamottin