Potential Implications of Quercetin and its Derivatives in Cardioprotection

Abstract

Quercetin (QCT) is a natural polyphenolic compound enriched in human food, mainly in vegetables, fruits and berries. QCT and its main derivatives, such as rhamnetin, rutin, hyperoside, etc., have been documented to possess many beneficial effects in the human body including their positive effects in the cardiovascular system. However, clinical implications of QCT and its derivatives are still rare. In the current paper we provide a complex picture of the most recent knowledge on the effects of QCT and its derivatives in different types of cardiac injury, mainly in ischemia-reperfusion (I/R) injury of the heart, but also in other pathologies such as anthracycline-induced cardiotoxicity or oxidative stress-induced cardiac injury, documented in in vitro and ex vivo, as well as in in vivo experimental models of cardiac injury. Moreover, we focus on cardiac effects of QCT in presence of metabolic comorbidities in addition to cardiovascular disease (CVD). Finally, we provide a short summary of clinical studies focused on cardiac effects of QCT. In general, it seems that QCT and its metabolites exert strong cardioprotective effects in a wide range of experimental models of cardiac injury, likely via their antioxidant, anti-inflammatory and molecular pathways-modulating properties; however, ageing and presence of lifestyle-related comorbidities may confound their beneficial effects in heart disease. On the other hand, due to very limited number of clinical trials focused on cardiac effects of QCT and its derivatives, clinical data are inconclusive. Thus, additional well-designed human studies including a high enough number of patients testing different concentrations of QCT are needed to reveal real therapeutic potential of QCT in CVD. Finally, several negative or controversial effects of QCT in the heart have been reported, and this should be also taken into consideration in QCT-based approaches aimed to treat CVD in humans.

Keywords: QCT derivatives; cardioprotection; quercetin (QCT).

Figure 1

Chemical structures of: (A) flavone backbone with potential substituent sites; (B) QCT.

Figure 2

Overview of QCT metabolization in the body. QCT and its monosaccharide* derivatives (including QCT glucoside**) are metabolized in small intestine. After a chain of reactions catalyzed by enzymes UGT, SULT or COMT causing glucoronidation, sulfation or methylation, respectively, QCT metabolites are either transported by ABC transporters to the portal vein and then to liver or re-uptake and transport back to the intestinal lumen by MRP-2, continuing to the large intestine. QCT aglycone as a possible product of QCT glycosides and QCT glucosides is transferred by passive diffusion through enterocytes to hepatic portal vein and consequently to the liver. In the large intestine, mainly QCT oligosaccharides and polysaccharides (QCT glycosides***) are enzymatically deglycosylated to QCT aglycone, which is transported from intestinal lumen to portal vein by passive diffusion through colonocytes. Degradation of QCT metabolites, which were transported from the small intestine to the large intestine, occurs in the large intestinal lumen, where they are degraded to phenolic acids. In the liver, further metabolization of thus far created QCT metabolites or QCT aglycone occurs by their conjugation (by UGT or SULT) or modification (by COMT). Finally, QCT metabolites are transported from liver to either systemic circulation or back to duodenum (small intestine) via bile, possibly heading to large intestinal final degradation. For more details, see Chapter 2.2.

Figure 3

Scheme of potential cardioprotective effects of QCT and its derivatives in heart injury outlining the proposed molecular mechanisms involved in their action.