An update on polyphenol disposition via coupled metabolic pathways

ABSTRACT

Introduction: Polyphenols, which are widely distributed in plants and the human diets, are known to have numerous biological activities. However, the low bioavailability of polyphenols is mediated by coupled metabolic pathways.

Areas covered: The key role of the interplay between drug metabolic enzymes (DMEs) and efflux transporters (ETs), nuclear receptors (NRs), and intestinal microflora in the disposition of polyphenols is summarized.

Expert opinion: ETs are shown to act as a ‘revolving door’, facilitating and/or controlling cellular polyphenol glucuronide/sulfate excretion. Elucidating the mechanisms underlying the glucuronidation/sulfation–transport interplay and structure-activity relationships (SAR) of glucuronide/sulfate efflux by an ET is important. Some new physiologically based pharmacokinetic (PBPK) models could be developed to predict the interplay between glucuronides/sulfates and ETs. Additionally, the combined actions of uridine-5′-diphosphate glucuronosyltransferases, ETs, and intestinal microflora/enterocyte-derived β-glucuronidase enable triple recycling (local, enteric, and enterohepatic recycling), thereby increasing the residence time of polyphenols and their glucuronides in the local intestine and liver. Further studies are necessary to explore these recycling mechanisms and interactions between polyphenols and the intestinal microbiota. Since NRs govern the inducible expression of target genes that encode DMEs and ETs. Determination of the regulation mechanism mediated by NRs using transgenic and knockout animals is still needed.

KEYWORDS:

• Drug metabolic enzymes
• efflux transporters
• intestinal microbiota
• nuclear receptors
• polyphenols

Article highlights

1. The coupling of DMEs and ETs is mainly responsible for the low bioavailability of polyphenols. ETs act as a ‘revolving door’ to control cellular polyphenol glucuronide/sulfate excretion.

2. The combined actions of UGTs, ETs, and intestinal microflora/enterocyte-derived β-glucuronidase enable the triple recycling of polyphenols in vivo.

3. It is important to determine the mechanism behind the NR-mediated regulation of DMEs and ETs.

4. Polyphenols can be metabolized by the intestinal microbiota, which indirectly affects their bioavailabilities.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Key International Joint Research Project of National Science Foundation of China (Grant 81720108033), the Natural Science Foundation of Guangdong Province (Grant 2015A030312012) and the Science and technology Project of Guangdong Province (Grant 201509010004).