4‐Methylcatechol, a Flavonoid Metabolite with Potent Antiplatelet Effects

Abstract

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.

A Mixture of Phenolic Metabolites of Quercetin Can Decrease Elevated Blood Pressure of Spontaneously Hypertensive Rats Even in Low Doses

“…Further experiments are necessary to elucidate these mechanisms in detail, and thus likely to explain why some combinations are more effective than others. It is of note that the pharmacological activity of 4MC is multifarious probably because it can interfere with Ca-trafficking, as was observed in platelets [13]. It is also of interest that the most potent combination tested in this study is based on compounds with contrasting mechanisms of action since 4MC acts NO-and endothelium-independently while the 3HPPA clearly depends on these factors.…”

Testing the Pharmacokinetic Interactions of 24 Colonic Flavonoid Metabolites with Human Serum Albumin and Cytochrome P450 Enzymes

“…Some colonic flavonoid metabolites (e.g., 33HPPA, 34DHPAA, 4-MC, and DESMA) may contribute to the positive cardiovascular effects of flavonoids [28,[73][74][75]. Considering the potential pharmacological importance of microbial flavonoid metabolites, a deeper understanding of their pharmacokinetic interactions is needed and reasonable.…”

Microbial Metabolites of Flavan-3-Ols and Their Biological Activity

“…Similarly, 4-methylcatechol has been reported to also have anti-platelet effects [60]. When testing its effect on whole blood platelet aggregation induced by arachidonic acid, this metabolite was much more active than acetylsalicylic acid (IC 50 = 3 µM vs. IC 50 = 25 µM, respectively) [60].…”

“…When testing its effect on whole blood platelet aggregation induced by arachidonic acid, this metabolite was much more active than acetylsalicylic acid (IC 50 = 3 µM vs. IC 50 = 25 µM, respectively) [60]. This could be confirmed by the authors in an ex ovo thrombotic model that mimics the in vivo situation [60]. Moreover, 4-methylcatechol was shown to interfere with calcium intracellular trafficking, and this seemed to be its main mechanism of action.…”

“…Moreover, 4-methylcatechol was shown to interfere with calcium intracellular trafficking, and this seemed to be its main mechanism of action. As the authors suggest, the methyl group probably does not play any role in the anti-platelet potential, but the hydroxyl groups in positions 1 and 2 seem to be important [60].…”