Abstract
Several medical plants, such as Passiflora incarnata L., contain C-glycosylated flavonoids, which may contribute to their efficacy. Information regarding the bioavailability and metabolism of these compounds is essential, but not sufficiently available. Therefore, the metabolism of the C-glycosylated flavones orientin, isoorientin, schaftoside, isoschaftoside, vitexin, and isovitexin was investigated using the Caco-2 cell line as an in vitro intestinal and epithelial metabolism model. Isovitexin, orientin, and isoorientin showed broad ranges of phase I and II metabolites containing hydroxylated, methoxylated, and sulfated compounds, whereas schaftoside, isoschaftoside, and vitexin underwent poor metabolism. All metabolites were identified via UHPLC-MS or UHPLC-MS/MS using compound libraries containing all conceivable metabolites. Some structures were confirmed via UHPLC-MS experiments with reference compounds after a cleavage reaction using glucuronidase and sulfatase. Of particular interest is the observed cleavage of the C–C bonds between sugar and aglycone residues in isovitexin, orientin, and isoorientin, resulting in unexpected glucuronidated or sulfated luteolin and apigenin derivatives. These findings indicate that C-glycosidic flavones can be highly metabolized in the intestine. In particular, flavonoids with ortho-dihydroxy groups showed sulfated metabolites. The identified glucuronidated or sulfated aglycones demonstrate that enzymes expressed by Caco-2 cells are able to potentially cleave C–C bonds in vitro.
Highlights
Results on the metabolism of C-glycosides are still lacking, as the metabolic profiles of C-glycosides have not been published to date
C-glycosides with human fecal samples has indicated that they can be deglycosylated in the colon by human intestinal bacteria to release the corresponding aglycones
To guarantee the stability of all test substances during the metabolism assay on Cacocells, they were incubated in the test buffer under assay conditions
Summary
Flavonoids are the most abundant class of secondary natural compounds in P. incarnata, representing up to 2.5% of the dried plant; they are potentially co-responsible for the plant’s pharmacological effects [2,3,4], and possibly have a prodrug effect requiring metabolic activation [5]. Many naturally found flavonoids are glycosides, varying in sugar moiety and binding type. Most of them exist as O-glycosides, and the sugar is linked to the aglycone via an O-glycosidic bond. The predominant flavonoids found in the aerial parts of P. incarnata L. are C-glycosidic flavonoids, showing a C–C glycosidic bond between the sugar and the C-8 or C-6 positions of the aglycones apigenin and luteolin [6]. Positive effects on human health are expected, but unexplored
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