Editorial pubs.acs.org/molecularpharmaceutics
Bioavailability of Polyphenols and Flavonoids in the Era of Precision Medicine
T
en years ago, Molecular Pharmaceutics (Volume 4, issue 6) published a special issue devoted to bioavailability of flavonoids and polyphenols. At that time, many of the mysteries surrounding poor bioavailabilities of polyphenols were yet to be resolved and the editorial asked for more resources to be devoted to solve this problem.1 Ten years later, major progress has been made in understanding the causes of their poor oral bioavailabilities (some of which will be published in this special issue), although we still lack practical solutions to the problem of poor oral bioavailabilities. A significant recent event in the use of polyphenols as pharmaceuticals was marked by the 2012 FDA approval of crofelemer (an oligomeric proanthocyanidin) for managing side effects of certain HIV drugs. This follows an earlier approval of Polyphenon E (a green tea polyphenol mixture) for genital warts in 2006. Whereas these approvals improve the chances for the increased use of polyphenols as drugs, none of the drugs are designated for systemic delivery. Thus, the solutions to their bioavailability problems continue to elude us. Despite the misgivings about their bioavailabilities, natural or dietary polyphenols (e.g., genistein, curcumin, and resveratrol) used to and continue to receive enormous attention because of their potential health benefits (e.g., anti-inflammatory, antiaging, anticancer, and cholesterol-lowering).2−4 The fact that polyphenols will interact with so many targets continues to attract researchers to this field, especially using in vitro models. These continued interests raise two legitimate questions: (1) how could we achieve precision medicine with polyphenols if we cannot pinpoint its precise in vivo target(s), and (2) what are our options if consistent and high systemic exposures to polyphenols are not achievable? To answer these questions, we need to examine the history of polyphenols and their potentials as drugs and healthpromoting agents. Chemically, polyphenols are a group of compounds featured by the presence of multiple phenolic groups.5 They are widely distributed in the plant world and are responsible for giving beautiful colors to the plant world. Humans have consumed polyphenols since the beginning of time, and today these molecules are widely consumed as a part of diet and/or nutritional supplements.6,7 Although it is hard to find the exact reasons why people consume them as nutritional supplements, anecdotal evidence suggests that broad media coverage and favorable epidemiological study results together with our desire to identify simple, convenient, and inexpensive ways to remain healthy may have driven the behavior. Why are scientists driven to study polyphenols? Perhaps they are just curious; are polyphenols really beneficial for humans as all the newspaper articles tend to suggest? Others are driven by epidemiological studies that have shown that certain types of food are considered to be healthier than others. A case in a point is the story of genistein, a soy isoflavone. It was found in the 1980s that the Japanese population has lower incidence of prostate and breast cancer than their counterparts (same racial and genetic background) in the United States, which led to the © 2017 American Chemical Society
analysis of the differences in diet. Eventually, genistein, an isoflavone commonly found in Japanese food but absent from a typical American diet, was discovered. Genistein is one of the first non-cytotoxic tyrosine kinase inhibitors that can suppress cancer cell growth, and more than 10,000 citations can be found in PubMed using genistein as a key word. It took two more decades for the first tyrosine kinase inhibitor to become a drug, and today there are more than 30 FDA-approved kinase inhibitors on the market. Hence, another reason that drove scientists is because plant-derived polyphenols are available and affordable, and at certain concentrations they can hit a desired target without killing the cells in vitro. These targets can be further verified before a drug development effort is launched. It is quite clear from earlier discussions that both the public and scientists are attracted to polyphenols present in food and diet. Many people believe that the findings from in vitro molecular biological studies will translate into health-promoting effects in vivo. For example, resveratrol was once called an antiaging agent because it inhibits cAMP-dependent phosphodiesterases, which are capable of triggering a cascade of events that ameliorate the symptoms of metabolic diseases associated with aging.8 However, compared with the well-documented effects of dietary polyphenols in vitro, their effects in vivo are limited and vague.9 One of the main reasons for this discrepancy (i.e., in vitro vs in vivo) is that the in vivo exposure levels of the polyphenols are inconsistent and much lower than the effective concentrations derived from the in vitro studies.9 In other words, inconsistent and low systemic exposure or poor oral bioavailability greatly limits the therapeutic uses of dietary polyphenols.10 What are the causes of poor bioavailabilities? It is well-known that the first-pass metabolism involving phase II conjugation (i.e., glucuronidation and/or sulfonation) of polyphenols is the leading cause of their poor bioavailabilities.10 Phase II metabolism reactions are catalyzed by phase II enzymes (e.g., UDP-glucuronosyltransferases/UGTs and sulfotransferases/ SULTs) to produce highly hydrophilic conjugates (e.g., glucuronides and sulfates),11 facilitating their excretion from the body.12 More recently (since 2007), it has become increasingly clear that efflux transporters (e.g., BCRP and MRPs), which facilitate the removal of hydrophilic phase II conjugates, play a critical role in determining the pharmacokinetics and bioavailability of dietary polyphenols.13−15 Failed or inefficient excretion of these metabolites will have a negative effect on overall cellular metabolism, leading to a higher exposure of parent molecule.16 This is because intracellular accumulation of phase II metabolites favors the deconjugation reactions (e.g., β-glucuronidase-mediated deglucuronidation and arylsulfatase B-mediated desulfation) that convert the Special Issue: Bioavailability of Polyphenols and Flavonoids in the Era of Precision Medicine Published: September 5, 2017 2861
DOI: 10.1021/acs.molpharmaceut.7b00545 Mol. Pharmaceutics 2017, 14, 2861−2863
Molecular Pharmaceutics
Editorial
metabolites back to parent molecules,17,18 thereby resulting in reduced overall metabolism.16 Is it possible to predict polyphenol bioavailability in vivo? Whereas the association of polyphenol bioavailability with both phase II enzymes and efflux transporters has been well established, predicting and improving the bioavailability of polyphenols is very difficult. For example, none of the current software packages (e.g., GastroPlus, SymCyp) can reliably project their bioavailabilities in humans. This lack of predictable bioavailability creates significant challenges for the use of the precision medicine approach to promote the use of polyphenols in humans. This is because we cannot adequately test the effectiveness of an agent if we cannot improve its bioavailability to consistent levels (usually >50%). We believe that more development in this area of research is critical if we were to use the precision medicine principle to derive greater benefit for humans when polyphenols are used for health-promoting and pharmacological purposes. Will polyphenols (including flavonoids) move beyond systemic circulation to exert their bioactivities if their bioavailabilities are so poor? Ten years ago, the answer would have been no. However, more recent studies in the CNS system indicated the presence of charged flavonoid conjugates in the brain and that these charged flavonoid molecules are biologically active.19 These exciting data suggest that we are moving the research of flavonoids’ bioavailability into a new territory, where CNS diseases can be the ultimate target of conjugated polyphenols.20 Considering that many of the neurodegenerative diseases are affecting millions of our elderly, this field of research may generate great discovery that can lead to the development of new drugs and nutritional supplements. What can we do to move the field forward so that one day many humans can take a pill that is as effective as a large amount of fresh produce and fruits? We believe that progresses in applying the principles of precision medicine will drive the study of polyphenols, and vice versa. This is because we are going to have comprehensive “big data” about human health, as the cost of a whole genome sequence of a typical human is within $1000 now (https://www.genome.gov/ sequencingcosts/), and will be within $300 soon. With rapid advances in epigenetics, there is a possibility that one day we can easily predict the functions of every relevant enzyme and transporter. We could then measure the role of an efflux transporter in determining the transport of a glucuronide and if a polyphenol aglycon at low but sustained concentration is truly beneficial. In the meantime, many scientists will continue work to elucidate the roles played by different transporters and enzymes in the metabolism and disposition of polyphenols. This will build on some of our major achievements in the past decade: (1) elucidating quantitative or qualitative structure− activity relationships for phase II enzymes (UGTs and SULTs);21,22 (2) revealing the importance of efflux transporters such as BCRP23 and MRP2;24 and (3) elucidating that phase II enzymes and efflux transporters are regulated at both transcriptional and posttranscriptional levels.25−28 Lastly, on the extraordinarily hot issue of polyphenol benefits, we must also ask for precaution and remember the dangers posed by consumption of excessive amounts of purified natural polyphenols. Whereas it is rare in developed countries that polyphenols are used in intravenous or intramuscular injections, polyphenols/phenolics are often a part of herbal extracts that are used in some of the most rapidly developing and densely populated countries such as China. In contrast,
many developed countries sell large quantities of highly purified polyphenols as supplements with minimal regulations. There is increasing evidence that neither approach is always safe.29 Too much antioxidants will likely make them pro-oxidants, whereas mixing prescription drugs with polyphenols has been reported to cause unfavorable drug−polyphenol interactions that lead to increased toxicity.29 In this special issue of Molecular Pharmaceutics, several papers highlight the roles of enzymes and transporters in flavonoid disposition whereas others determine the possible side effects with using large quantities of plant polyphenols/phenolics. Troberg et al. demonstrated that the role of UGT1A10 (an enzyme known to metabolize polyphenols) in intestinal glucuronidation was underestimated due to poor enzymatic activity of commercial UGT1A10 preparation. Yu et al. show that SULTs and BCRP work together in metabolism and elimination of calycosin (a natural flavonoid derived from the dry root extract of Radix Astragali). Dong et al. developed a more bioavailable formulation (nanoemulsion) for chrysin by including a UGT-inhibitory excipient sodium oleate, supporting a critical role for UGTs in determining flavonoid bioavailability. Lu et al. identified FXR, the bile acid-sensing receptor, as a novel transcriptional regulator of UGT2B10. This regulation may contribute to the large interindividual variation in hepatic expression of UGT2B10. Jones et al. showed that dietary flavonoids were found to be inhibitors (and potential substrates) of monocarboxylate transporter 6 (MCT6). These inhibitory effects may impact the pharmacokinetics and pharmacodynamics of MCT6-specific substrates including flavonoids themselves. Ye et al. showed that intravenous administered flavonoid eriodictyol decreased acetaminopheninduced hepatotoxicity, consistent with the commonly believed view that flavonoids are good for human health but poor bioavailability rendered them ineffective via oral administration. In contrast, Ma et al. reported a potential mechanism by which plant polyphenolic acids could affect the metabolism of bilirubin and cause liver toxicity, suggesting that not all polyphenols and their analogues are safe to use without regard to their structures and quantity of use. Despite the poor bioavailability and perhaps poor CNS penetration, Fong et al. studied brain uptake of bioactive flavones and their anxiolytic effects. The authors found that bioactive flavone oroxylin A in Scutellariae Radix (SR) had the highest brain uptake but suppressed the anxiolytic effects of the other flavones, accounting for the lack of overall anxiolytic effect of SR extract. Liu et al. determined the expression levels of various Ugts and Sults involved in the phase II metabolism in mice, providing valuable quantitative information about these enzymes that will aid the development of physiologically based pharmacokinetic (PB−PK) models. Lastly, Ge et al. proposed a transport− glucuronidation classification system that can be used to predict the impact of transporters on disposition of glucuronides. The ability of transport/metabolism-based classification system to accurately predict polyphenol disposition emphasizes the essential roles of both enzymes and transporters in determining polyphenol bioavailability.
Ming Hu,* Guest Editor
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030, United States
Baojian Wu,* Guest Editor 2862
DOI: 10.1021/acs.molpharmaceut.7b00545 Mol. Pharmaceutics 2017, 14, 2861−2863
Molecular Pharmaceutics
Editorial
(12) Rowland, A.; Miners, J. O.; Mackenzie, P. I. The UDPglucuronosyltransferases: their role in drug metabolism and detoxification. Int. J. Biochem. Cell Biol. 2013, 45 (6), 1121−32. (13) Xu, H.; Kulkarni, K. H.; Singh, R.; Yang, Z.; Wang, S. W.; Tam, V. H.; Hu, M. Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides. Mol. Pharmaceutics 2009, 6 (6), 1703−15. (14) Yang, Z.; Zhu, W.; Gao, S.; Yin, T.; Jiang, W.; Hu, M. Breast cancer resistance protein (ABCG2) determines distribution of genistein phase II metabolites: reevaluation of the roles of ABCG2 in the disposition of genistein. Drug Metab. Dispos. 2012, 40 (10), 1883−93. (15) Quan, E.; Wang, H.; Dong, D.; Zhang, X.; Wu, B. Characterization of chrysin glucuronidation in UGT1A1-overexpressing HeLa cells: elucidating the transporters responsible for efflux of glucuronide. Drug Metab. Dispos. 2015, 43 (4), 433−43. (16) Wang, S.; Xing, H.; Zhao, M.; Lu, D.; Li, Z.; Dong, D.; Wu, B. Recent Advances in Understanding of Kinetic Interplay Between Phase II Metabolism and Efflux Transport. Curr. Drug Metab. 2016, 17 (10), 922−929. (17) Sun, H.; Zhou, X.; Zhang, X.; Wu, B. Decreased Expression of Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) Leads to Reduced Glucuronidation of Flavonoids in UGT1A1-Overexpressing HeLa Cells: The Role of Futile Recycling. J. Agric. Food Chem. 2015, 63 (26), 6001−8. (18) Zhao, M.; Wang, S.; Li, F.; Dong, D.; Wu, B. Arylsulfatase B Mediates the Sulfonation-Transport Interplay in Human Embryonic Kidney 293 Cells Overexpressing Sulfotransferase 1A3. Drug Metab. Dispos. 2016, 44 (9), 1441−9. (19) Pogacnik, L.; Pirc, K.; Palmela, I.; Skrt, M.; Kim, K. S.; Brites, D.; Brito, M. A.; Ulrih, N. P.; Silva, R. F. Potential for brain accessibility and analysis of stability of selected flavonoids in relation to neuroprotection in vitro. Brain Res. 2016, 1651, 17−26. (20) Andrade, P. B.; Grosso, C.; Valentao, P.; Bernardo, J. Flavonoids in Neurodegeneration: Limitations and Strategies to Cross CNS Barriers. Curr. Med. Chem. 2016, 23 (36), 4151−4174. (21) Dong, D.; Ako, R.; Hu, M.; Wu, B. Understanding substrate selectivity of human UDP-glucuronosyltransferases through QSAR modeling and analysis of homologous enzymes. Xenobiotica 2012, 42 (8), 808−20. (22) Sharma, V.; Duffel, M. W. A comparative molecular field analysis-based approach to prediction of sulfotransferase catalytic specificity. Methods Enzymol. 2005, 400, 249−63. (23) Wei, Y.; Wu, B.; Jiang, W.; Yin, T.; Jia, X.; Basu, S.; Yang, G.; Hu, M. Revolving door action of breast cancer resistance protein (BCRP) facilitates or controls the efflux of flavone glucuronides from UGT1A9-overexpressing HeLa cells. Mol. Pharmaceutics 2013, 10 (5), 1736−50. (24) Williamson, G.; Aeberli, I.; Miguet, L.; Zhang, Z.; Sanchez, M. B.; Crespy, V.; Barron, D.; Needs, P.; Kroon, P. A.; Glavinas, H.; Krajcsi, P.; Grigorov, M. Interaction of positional isomers of quercetin glucuronides with the transporter ABCC2 (cMOAT, MRP2). Drug Metab. Dispos. 2007, 35 (8), 1262−8. (25) Hu, D. G.; Meech, R.; McKinnon, R. A.; Mackenzie, P. I. Transcriptional regulation of human UDP-glucuronosyltransferase genes. Drug Metab. Rev. 2014, 46 (4), 421−58. (26) Kodama, S.; Negishi, M. Sulfotransferase genes: regulation by nuclear receptors in response to xeno/endo-biotics. Drug Metab. Rev. 2013, 45 (4), 441−9. (27) Riches, Z.; Collier, A. C. Posttranscriptional regulation of uridine diphosphate glucuronosyltransferases. Expert Opin. Drug Metab. Toxicol. 2015, 11 (6), 949−65. (28) Klaassen, C. D.; Aleksunes, L. M. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev. 2010, 62 (1), 1−96. (29) Margina, D.; Ilie, M.; Gradinaru, D.; Androutsopoulos, V. P.; Kouretas, D.; Tsatsakis, A. M. Natural products-friends or foes? Toxicol. Lett. 2015, 236 (3), 154−67.
College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China
Zhongqiu Liu,* Guest Editor
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International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Ming Hu: 0000-0003-0606-2336 Baojian Wu: 0000-0003-4629-5142 Zhongqiu Liu: 0000-0001-6986-9677 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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ACKNOWLEDGMENTS M.H. is supported by a NIH grant, NIGMS070737. Z.Q.L. is supported by the grants of National Natural Science Foundation of China [81503466], the Science and Technology Project of Guangzhou City [201509010004], and the Guangdong Natural Science Foundation [2015AD030312012]. B.W. is supported by the National Natural Science Foundation of China [81573488].
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REFERENCES
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DOI: 10.1021/acs.molpharmaceut.7b00545 Mol. Pharmaceutics 2017, 14, 2861−2863
