Natural polyphenol disposition via coupled metabolic pathways

Abstract

A major challenge associated with the development of chemopreventive polyphenols is the lack of bioavailability in vivo, which are primarily the result of coupled metabolic activities of conjugating enzymes and efflux transporters. These coupling processes are present in disposition tissues and organs in mammals and are efficient for the purposes of drug metabolism, elimination and detoxification. Therefore, it was expected that these coupling processes represent a significant barrier to the oral bioavailabilities of polyphenols. In various studies of this coupling process, it was identified that various conjugating enzymes such as uridine 5'-diphosphate-glucuronosyltransferase and sulfotransferase are capable of producing very hydrophilic metabolites of polyphenols, which cannot diffuse out of the cells and needs the action of efflux transporters to pump them out of the cells. Additional studies have shown that efflux transporters, such as multi-drug resistance-associated protein 2, breast cancer-resistant protein and the organic anion transporters, appear to serve as the gate keeper when there is an excess capacity to metabolise the compounds. These efflux transporters may also act as the facilitator of metabolism when there is a product/metabolite inhibition. For polyphenols, these coupled processes enable a duo recycling scheme of enteric and enterohepatic recycling, which allows the polyphenols to be reabsorbed and results in longer than expected apparent plasma half-lifes for these compounds and their conjugates. Because the vast majority of polyphenols in plasma are hydrophilic conjugates, more research is needed to determine if the metabolites are active or reactive, which will help explain their mechanism of actions.

Fig. 1. A. Chemical structures of polyphenols. B. Chemical structures of flavonoids

Fig. 1. A. Chemical structures of polyphenols. B. Chemical structures of flavonoids

Fig.2

Absorption and metabolism of genistein and genistin (@100 μM) in rat jejunum using single-pass perfusion (flow rate=0.191 ml/min). % Metabolized is calculated as the ratio of metabolite in outlet perfusate to parent drug concentration in inlet perfusate.

Fig.3

Intestinal glucuronidation rates measured using rat microsomes and intestinal excretion rates measured using perfused rat intestine. Each bar is the average of four determination for perfusion experiments. The metabolism rates were calculated using kinetic parameters obtained as described in Wang et al.

Fig. 4

A schematic representation of coupled efflux and metabolism.

Fig. 5

Schematic representation of the coupling theorem. Substrates are represented by triangles whereas products of enzymes or metabolites are represented by pentagons.

Fig. 6. Intestinal microsomes-catalyzed glucuronidation of formononetin and biochanin A (Panel A) glucuronides by intestine (Panel B). Concentration of isoflavone used in perfusion studies was 10 μM. Adapted from Jia et al.[86]

Fig. 7

Schematic representation of the more complex coupling theories. Substrates are represented by triangles whereas products of enzymes or metabolites are represented by other shapes. In this scheme, substances such drugs and nutrients will get in by passive diffusion or carried by transporter. The intake process at the apical side is often called uptake, whereas intake at the basolateral side is often a part of secretion. In contrast to intake, substances excreted by transporters out of the cells is called efflux. These efflux transporters can locate at either sides (apical or basolateral side). Some efflux transporters such as p-gp, MRP2, MRP4, and BCRP are generally present on the apical surface of the cells, whereas others such as MRP3, MRP5, MRP6 are localized on the basolateral of the cell. Some efflux transporters such as MRP1 and OATs are present on both apical and basolateral surfaces. Efflux transporters located at the apical side diminish absorption into the blood and facilitate excretion, whereas efflux transporters at the basolateral sides have the opposite functions.