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.