Anthocyanins and their metabolites are weak inhibitors of cytochrome P450 3A4

Abstract

The cytochrome P450 enzyme cytochrome P450 3A4 (CYP3A4) controls the metabolism of about 60% of all drugs, and its inhibition may dramatically affect drug safety. Modulation of cytochrome P450 activity has been observed by constituents of fruit extracts including several flavonoids. The present investigation addresses CYP3A4 inhibition by anthocyanins, their aglycons, proanthocyanidins, and phenolic metabolites using a chemiluminescent assay. Test compounds inhibited CYP3A4 activity in a concentration-dependent manner featuring IC(50) values from 12.2 up to 7,842 microM. In the order of decreasing effect size, anthocyanidins were followed by anthocyanins, proanthocyanidins, and phenolic acids. When compared to earlier data on furanocoumarins from grapefruit extract, the inhibitory activity of tested anthocyanins, and anthocyanidins was shown to be about 10,000-fold weaker, and was negligible for phenolic acids (>100 000-fold weaker). Future studies are invited to address effects of the above flavonoids on other CYP isoforms for more detailed toxicity profiles.

Three-dimensional quantitative structure–activity relationship and docking studies on a series of anthocyanin derivatives as cytochrome P450 3A4 inhibitors

“…Consequently, a model with r 2 of 0.66 was obtained for 16 compounds (Figure 6B), which indicates that the correlation was statistically significant, for the theoretical molecular docking study, thus demonstrating the applicability of this method. This model eventually confirmed the previous observations found in our CoMFA/CoMSIA models and previously published experimental results 14,42 that anthocyanin derivatives, generally occurring as 3-O-glycosides, have bioactivity attributable to the aglycone but not to the sugar moiety or other binding species.…”

“…In general, the maps represent a molecular state that is close to optimal for binding to the CYP3A4 protein when it was detected as IC 50 in the previous experiments. 14 The results of the CoMSIA analysis are shown in Tables 1 and 2. Similarly to the CoMFA model, we used the steric and electrostatic fields in the CoMSIA analysis.…”

“…14,18 The two-dimensional structures of the compounds were drawn using the MarvinSketch version 5.2 program (ChemAxon, Budapest, Hungary). After the two-dimensional sketches were converted into three-dimensional images, explicit hydrogen molecules were added and recorded in PDB (Protein Data Bank) format; 3D-QSAR modeling was done using Sybyl-X 1.1 software (Tripos International, St Louis, MO, USA).…”

“…14 The antimutagenic activity of anthocyanidins was earlier established by Gasiorowski et al, whose results revealed that these compounds, isolated from the fruit of Aronia melanocarpa, sufficiently inhibit the mutagenic activity of benzo(a) pyrene and 2-aminofluorene in the Ames test. 16 Hence, CYP inhibition by anthocyanin compounds might be considered as antimutagenic, given that these enzymes contribute to carcinogenesis in several organs [17][18][19][20] and increase DNA toxicity and damage.…”

“…12 Several flavonoids have been shown to modulate the CYP system and alter the pharmacokinetics and pharmacodynamics of many commonly prescribed drug substances. 13,14 These water-soluble glycosidic derivatives of flavylium salts are most prevalent in various fruit and vegetables, such as cabbage, grapes, and berries. 15 It was previously reported by Dreiseitel et al that CYP3A4 inhibition by a series of anthocyanin derivatives, including their aglycones and proanthocyanidins, is achieved in a concentration-dependent manner.…”