No abstract

Background and purpose: Dietary anthocyanins hold great promise in the prevention of chronic disease but factors affecting their bioavailability remain poorly defined. Specifically, the role played by transport mechanisms at the intestinal and blood-brain barriers (BBB) is currently unknown. Experimental approach: In the present study, 16 anthocyanins and anthocyanidins were exposed to the human efflux transporters multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), using dye efflux, ATPase and, for BCRP, vesicular transport assays. Key results: All test compounds interacted with the BCRP transporter in vitro. Of these, seven emerged as potential BCRP substrates (malvidin, petunidin, malvidin-3-galactoside, malvidin-3,5-diglucoside, cyanidin-3-galactoside, peonidin-3-glucoside, cyanidin-3-glucoside) and 12 as potential inhibitors of BCRP (cyanidin, peonidin, cyanidin-3,5-diglucoside, malvidin, pelargonidin, delphinidin, petunidin, delphinidin-3-glucoside, cyanidin-3-rutinoside, malvidin-3-glucoside, pelargonidin-3,5-diglucoside, malvidin-3-galactoside). Malvidin, malvidin-3-galactoside and petunidin exhibited bimodal activities serving as BCRP substrates at low concentrations and, at higher concentrations, as BCRP inhibitors. Effects on MDR1, in contrast, were weak. Only aglycones exerted mild inhibitory activity. Conclusions and implications:Although the anthocyanidins under study may alter pharmacokinetics of drugs that are BCRP substrates, they are less likely to interfere with activities of MDR1 substrates. The present data suggest that several anthocyanins and anthocyanidins may be actively transported out of intestinal tissues and endothelia, limiting their bioavailability in plasma and brain.

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.

No abstract

No abstract

The cytochrome P450 enzyme CYP2C19 is involved in the metabolism of many commonly prescribed drugs, including proton pump inhibitors, antiepileptics and antidepressants. CYP2C19 inhibitors from food and food supplements may augment the toxicity of these agents and lead to noncompliance with treatment. The present investigation addresses CYP2C19 inhibition by 18 berry constituents using a chemiluminescent assay. Test compounds displayed inhibitory properties in a concentration-dependent fashion, with IC(50) values ranging from 20.2 microM up to >316 microM. In the order of decreasing effect size, anthocyanidins were followed by anthocyanidin-monoglycosides and procyanidins. Anthocyanidin-diglucosides exhibited weak and biphasic effects. When compared with the CYP2C19 inhibitor fluvoxamine, the flavonoids under study were 50- to 750-fold less potent. It is concluded that the above natural substances are moderate to poor inhibitors of CYP2C19 in vitro.

In order to study the human intestinal transit of flavan-3-ol C-glycosides, several C-glycosyl derivatives were prepared by non-enzymatic reaction of (+)-catechin with α-D-glucose, α-D-galactose and α-D-rhamnose, respectively. In contrast to literature data, we propose that the reaction mechanism proceeds in analogy to the rearrangement of flavan-3-ols during epimerization under alkaline conditions. Four of the 12 synthesized flavan-3-ol C-glycosides were incubated under aerobic conditions at 37°C using saliva (2 min) and simulated gastric juice (3 h). To simulate human intestine, the C-glycosides were also incubated under anaerobic conditions at 37°C both in human ileostomy fluid (10 h) and colostomy fluid (24 h), respectively. The flavan-3-ol C-glycosides under study, i.e. (+)-epicatechin 8-C-β-D-glucopyranoside (1a), (+)-epicatechin 6-C-β-D-glucopyranoside (1d), (+)-catechin 6-C-β-D-galactopyranoside (2b), (+)-catechin 6-C-β-D-rhamnopyranoside (3b) were analyzed in the incubation samples by HPLC-DAD and HPLC-DAD-MS/MS. They were found to be stable in the course of incubation in saliva, simulated gastric juice and ileostomy fluid and underwent degradation in colostomy fluid. While the 6-C-β-D-glucopyranoside 1d was completely metabolized between 2 and 4 h, decomposition of the 6-C-β-D-galactopyranoside 2b reached only 16 ± 2% within 4 h of incubation. Linear degradation rates of 1d and 2b in colostomy fluid differed significantly. As microbial metabolism of flavan-3-ols is known not to be influenced by the stereochemistry of the aglycon, varying degradation rates are ascribed to the effect of the sugar moiety. Based on these results we assume that flavan-3-ol C-glycosides pass through the upper gastrointestinal tract (oral cavity, stomach and small intestine) unmodified and are then metabolized by the colonic microflora.

Epidemiological studies suggest that nutritional antioxidants may reduce the incidence of neurodegenerative disorders and age-related cognitive decline. Specifically, protection against oxidative stress and inflammation has served as a rationale for promoting diets rich in vegetables and fruits. The present study addresses secretory phospholipase A(2) (sPLA(2)) as a novel candidate effector of neuroprotection conferred by anthocyanins and anthocyanidins. Using a photometric assay, 15 compounds were screened for their ability to inhibit PLA(2). Of these, cyanidin, malvidin, peonidin, petunidin, and delphinidin achieved K(i) values