Fungal lactone ring opening of 6', 7'-dihydroxybergamottin diminishes cytochrome P450 3A4 inhibitory activity

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

Submitted to: Subtropical Technology Conference Proceedings
Publication Type: Abstract Only
Publication Acceptance Date: 10/18/2009
Publication Date: 10/22/2009
Citation: Myung, K., Manthey, J., Narciso, J. 2009. Lactone ring opening of 6', 7'-dihydroxybergamottin by citrus-pathogenic fungi diminishes its cytochrome P450 3A4 inhibitory activity. Subtropical Technology Conference Proceedings. 60:12.

Interpretive Summary:

Technical Abstract: Furanocoumarins (FCs) are a class of aromatic compounds in grapefruit that inhibit human intestinal cytochrome P450 3A4 (CYP3A4). Since fungi metabolize polycyclic aromatic hydrocarbons, we hypothesized that certain fungi might also metabolize FCs into forms that may be inactive as CYP3A4 inhibitors in the “grapefruit-drug interactions”. Six citrus-pathogenic fungi were observed to metabolize 6', 7'-epoxybergamottin (1) into three major metabolites, including 6', 7'-dihydroxybergamottin (2), bergaptol (3), and an unknown compound, 4-(6´, 7´-dihydroxygeranyloxy)-5-(2''-carboxyethyl)-6-hydroxybenzofuran (4). The compound 4 was also found to be a major metabolite of compound 2, where the lactone ring of compound 1 was reduced and cleaved. In Table 1, the compound 4 showed poor inhibitory activity against CYP3A4 (IC50 > 172.0 µM), compared to the known inhibitor 2 (IC50 = 0.81 µM). These results demonstrate a potential use of the fungal enzymes to make the grapefruit FCs inactive.