SCOPE: Intake of flavonoids from the diet can be substantial, and epidemiological studies suggest that these compounds can decrease the incidence of cardiovascular diseases by involvement with increased platelet aggregation. Although parent flavonoids possess antiplatelet effects, the clinical importance is disputable due to their very low bioavailability. Most of them are metabolized by human colon bacteria to smaller phenolic compounds, which reach higher plasma concentrations than the parent flavonoids. In this study, a series of 29 known flavonoid metabolites is tested for antiplatelet potential. METHODS AND RESULTS: Four compounds appear to have a biologically relevant antiplatelet effect using whole human blood. 4-Methylcatechol (4-MC) is clearly the most efficient being about 10× times more active than clinically used acetylsalicylic acid. This ex vivo effect is also confirmed using a potentially novel in-vivo-like ex ovo hen's egg model of thrombosis, where 4-MC significantly increases the survival of the eggs. The mechanism of action is studied and it seems that it is mainly based on the influence on intracellular calcium signaling. CONCLUSION: This study shows that some flavonoid metabolites formed by human microflora have a strong antiplatelet effect. This information can help to explain the antiplatelet potential of orally given flavonoids.
- MeSH
- Platelet Aggregation drug effects MeSH
- Platelet Aggregation Inhibitors pharmacology MeSH
- Cyclooxygenase Inhibitors pharmacology MeSH
- Enzyme Inhibitors pharmacology MeSH
- Catechols pharmacology MeSH
- Chick Embryo MeSH
- Arachidonic Acid pharmacology MeSH
- Humans MeSH
- Drug Evaluation, Preclinical methods MeSH
- Pyrogallol pharmacology MeSH
- Serotonin metabolism MeSH
- Thromboxane-A Synthase antagonists & inhibitors MeSH
- Thrombosis drug therapy MeSH
- Animals MeSH
- Check Tag
- Chick Embryo MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Pyrogallol is a polyphenol that generates the superoxide anion. In this study, we investigated the influence of pyrogallol on human platelets. Our data showed that exposure of platelets to pyrogallol induced numerous manifestations of apoptosis including depolarization of mitochondrial inner membrane and release of cytochrome c from the mitochondria. Pyrogallol also induced downstream extra-mitochondrial apoptotic responses, including activation of caspase-3 and phosphatidylserine exposure on the outer leaflet of the plasma membrane. Addition of glutathione significantly rescued cells from pyrogallol- induced apoptosis, as evidenced by a decrease of all markers of apoptosis. Thus, pyrogallol appears to produce depletion of intracellular glutathione content in platelets, the main non-protein antioxidant in the cells. Furthermore, inhibition of γ-glutamyl transpeptidase, an enzyme that plays the main role in the cellular supply of glutathione, reverted the glutathione (GSH) protection over platelet apoptosis. Our results indicate that pyrogallol induces apoptosis by suppressing the natural anti-oxidation in human platelets.
- MeSH
- Apoptosis drug effects MeSH
- Biomarkers metabolism MeSH
- Borates pharmacology MeSH
- Cytochromes c metabolism MeSH
- Glutathione pharmacology MeSH
- Humans MeSH
- Membrane Potential, Mitochondrial drug effects MeSH
- Pyrogallol pharmacology MeSH
- Serine pharmacology MeSH
- Blood Platelets cytology drug effects metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Epinephrine pharmacology MeSH
- Stress, Physiological metabolism MeSH
- Monoamine Oxidase Inhibitors MeSH
- Catecholamines metabolism MeSH
- Blood Glucose analysis MeSH
- Rats MeSH
- Humans MeSH
- Fatty Acids blood MeSH
- Pyrogallol pharmacology MeSH
- Transferases antagonists & inhibitors MeSH
- Tranylcypromine pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
