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

Authors: Myung, Kyung; Manthey, John; Narciso, Jan

Submitted to: Applied Microbiology and Biotechnology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/3/2007
Publication Date: 2/14/2008
Citation: Myung, K., Manthey, J.A., Narciso, J.A. 2008. Aspergillus niger metabolism of citrus furanocoumarin inhibitors of human cytochrome P450 3A4. Applied Microbiology and Biotechnology. 78:343-349.

Interpretive Summary: Furanocoumarins are a class of aromatic compounds found in plants. 6', 7'-epoxybergamottin (EB), 6', 7'-dihydroxybergamottin (DHB), and bergamottin (BM) are three major furanocoumarins in grapefruit that interfere with drug uptake. Up to date, there is no information on biotransformation of grapefruit furanocoumarins by microorganisms. Thus, we studied the biotransformation of furanocoumarins by fungi, and found that Aspergillus niger can metabolize the furanocoumarins into bergaptol-5-sulfate, a novel final product. In addition, the fungus had a capability of metabolizing non-grapefruit furanocoumarin, xanthotoxol, into xanthotoxol-8-sulfate. This will provide new insights into how fungi can metabolize some grapefruit and non-grapefruit furanocoumarins and perhaps alleviate the drug uptake problem.

Technical 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 important to the citrus industry is the furanocoumarins in grapefruit, and their metabolism in humans is critically involved in the "grapefruit/drug interactions". Thus far, the metabolism by fungi of the major furanocoumarins, including 6', 7'-epoxybergamottin (EB), 6', 7'-dihydroxybergamottin (DHB), and bergamottin (BM) has received little attention. In this study, the metabolism of EB, DHB, and BM by a number of fungi has been investigated. Of particular interest were the findings made with Aspergillus niger, which was observed to convert EB into several metabolites, DHB, bergaptol (BT), and a novel water-soluble conjugate (WSM). In addition, BM was hydrolyzed to BT, which was further metabolized to WSM. Structure of the novel WSM was identified as bergaptol-5-sulfate using mass spectrometry, UV absorption spectrum, chemical deconjugation, and 1H and 13C NMR spectroscopies, in which a sulfate group was attached to C5 of psoralen. Similarly, the fungus had a capability of metabolizing xanthotoxol, a structural isomer of BT, to a novel xanthotoxol-8-sulfate. A possible metabolic pathway by A. niger of furanocoumarin metabolism using unknown enzyme activities, such as a cleavage of a geranyl group by etherase-like enzyme and addition of a sulfate group by sulfotransferase-like enzyme, is discussed.