Current Drug Metabolism - Volume 14, Issue 4, 2013

Dietary isoflavones, popularly known as phytoestrogens, represent one of the most biologically active classes of flavonoids. Numerous in vitro and in vivo studies provide convincing evidence regarding their beneficial effects on human health. These isoflavones are increasingly being investigated as potential alternate therapies for a range of hormone-dependent conditions, including cancer, menopausal symptoms, osteoporosis and cardiovascular diseases. However, they exhibit poor oral bioavailability which limits their clinical utility in humans. The reason being, they are substrates of a plethora of enzymes and transporters and undergo extensive conjugative metabolism which facilitates their rapid elimination from biological systems. In addition, a number of experimental studies have also revealed that these isoflavones are potent inhibitors of various cytochrome P450 isoforms and transporters which play an important role in the disposition of many commonly prescribed drugs. Thus, there arise chances of observing clinically relevant herb-drug interactions which could sometimes be life-threatening. This review gives a comprehensive understanding of these dietary phytoestrogens with regard to their absorption, biodistribution and the role of enzyme-transporter interplay affecting their disposition in biological systems. Further, the effects of these phytoestrogens on the activity and kinetics of drug metabolizing enzymes and various clinically relevant influx/efflux transporters and the resulting diet-drug interactions have also been discussed.

Flavonoids undergo substantial hepatic metabolism and the metabolites might significantly contribute to the effects of these dietary constituents. The metabolites of flavonoids in liver can be summarized as follows: 1) For flavones, the hydroxylation appears to occur at the C-4'-, C-3&', C-6 and C-8- position when there is a single or no hydroxy group on the B-ring. The methoxyl groups positioned at the C-7, C-6 or C-4'- position of flavones are demethylated. The glucuronidation occurs at the 6, 7, 4' or 3'- hydroxyl moiety. Flavone glycosides and aglycones appear to undergo similar metabolic pathways. 2) For flavonols, the hydroxylation appears at the 3' and 4'- position and flavonols with a 4'-methoxy group are easily O-demethylated to their corresponding hydroxylated analogs. The glucuronidation takes place at the 7, 3, 3' and 4'- hydroxyl moiety. 3) For isoflavones, the microsomal hydroxylation is observed at the C-3'-, C-6 and C-8- position when there is a single or no hydroxy group on the B-ring. The demethylation takes place at the C-6- or C-4'- position when there is one methoxy group on C-4' or C-6-position, respectively. The glucuronidation occurs at the 4, or 5- hydroxyl moiety. 4) For chalcones, the C-3'-, and C-8- positions undergo hydroxylation. The C-8- position is a very active site for metabolism of chalcones.

Polyphenols are a versatile class of compounds that represent secondary metabolites from higher plants and which are abundantly present in the human diet. Epidemiological data suggest protective effects of polyhenols in relation to cancer, cardiovascular diseases, diabetes, infectious diseases and age-related conditions. HIV/AIDS remains prevalent in many parts of the world as acute infection and as anti-retroviral drug (ARV)–managed chronic disease. Due to the nature of the human immune deficiency virus (HIV) and an increased use of ARVs many drug-resistant HIV strains have emerged and continue to do so. This makes it impossible to rely on one standard drug treatment regime. This review summarizes anti- HIV activities of polyphenols. It highlights the diversity of modes of action by which polyphenols - according to their respective compound classes - exert their activities. Additionally, this review discusses polyphenols as multi-target anti-HIV agents and provides the context of in-vivo and clinical data. Based on the presented data, a three-pronged approach for further anti-HIV drug discovery is suggested applying methods of combinatorial medicinal chemistry on the diverse and sometimes unique scaffolds of polyphenols. The latter being selected according to the approach of ‘reverse pharmacology’ as a creative way to place safety and other clinical consideration at the beginning of the drug discovery- and development process.

The properties of polyphenols as AGEs formation inhibitors have attracted great interest among researchers. This review discusses the antiglycation activities of polyphenols and focuses on the relationship between the AGEs formation inhibitory activities and their chemical structures. The molecular structures influence the inhibition in the following ways: (1) The hydroxylation on both A ring and B ring improved the inhibitory activity on AGEs formation, while hydroxylation on C ring decreased the activity. (2) The methylation generally reduced the anti-AGEs activity of flavonoids, except for the 3-O-methylation of flavonols. (3) The glycosylation of hydroxyls of flavonoids tended to decrease the inhibitory activities on inhibiting AGEs formation, although contradictionary results were existed. (4) Hydrogenation of the C2=C3 double bond of flavones slightly weakened their activities. (5) A 5,7-dihydroxy structure was favorable to the activity of isoflavones. (6) Proanthocyanidins dimer or trimers showed a stronger inhibitory activity than catechins, and the glucosides of anthocyanidin had higher activities than their rutinosides. (7) The hydroxylation on B ring and the methylation of stilbenes decreased the inhibitory activity. (8) Presence of galloyl groups was important for the activity of catechins, and α-hydroxyl group at C-3 was much more effective than β-hydroxyl group at C-3. (9) The phenolic acids with multiple hydroxyls showed strong inhibition against AGEs formation, and an ortho or meta dihydroxyl structure on the benzene ring was vital to the anti-AGEs activity of anthraquinone. (10) Both ellagic acids and ellagitannins showed potent inhibitory activities on AGEs formation, and hydroxylation increased the activities but methylation decreased them.

The plant natural products known as polyphenols are found at micronutrient levels in fruits, vegetables, and plant-based beverages such as wine, tea, coffee and cocoa. Consumption of a fruit- and vegetable-rich diet, the “Mediterranean diet”, has been epidemiologically related to health benefits especially for chronic diseases including diabetes, cardiovascular disease, and Alzheimer’s disease. The abundance of polyphenols in plant-rich diets, and the potent bioactivities of polyphenols, provide indirect evidence for a role for polyphenols in maintaining good health. However, molecular mechanisms for therapeutic or preventative activity have not been demonstrated in vivo. We summarize the chemical classes of natural polyphenols, their bioactivities and bioavailability and metabolism. Because many polyphenols bind protein, we focus on the potential of protein binding to mediate the health-related effects of polyphenols. We discuss interactions with plasma proteins as the first target organ past the digestive tract for these orally-ingested compounds.

Tea materials are widely consumed beverages in the world and are a rich source of dietary polyphenols. Catechins found in tea show excellent antioxidant potential, which is beneficial for many diseases such as cancers and cardiovascular diseases. These Tea catechins can interact with plasma proteins to form soluble or insoluble complexes, which are responsible for their bioactivities in vivo. However, there is little review published recently which focused on tea catechins-plasma protein interaction (TcPI), despite numerous articles have appeared in this field. This review summarizes the recent trend in TcPI studies focusing on metabolism, structure-affinity relationship, influence on antioxidant activity, and molecular docking aspects.

Polyphenols are the most abundant antioxidants. Polyphenols are known to non-covalent interact with plasma proteins in blood through hydrophobic or hydrophilic interactions. It was found that the effect of polyphenol-plasma protein interaction (PpPI) on the bioavailability of polyphenols is not equivocal. Because the conclusion of individual reports are contradictory to each other; therefore, it is very difficult to give a univocal comment on the influence of PpPI on antioxidant property of polyphenols. The influence of PpPI on the antioxidant activity of polyphenols is decided by the antioxidant assay, the structure characteristics of polyphenols, as well as the proteins. This mini review mainly focused on the influence of PpPI on the antioxidant properties of polyphenols.

Phenolic compounds are commonly found in natural sources like plant-based foods and beverages. These compounds have received much attention due to their unique biological properties. Polyphenols possess a significant binding affinity for serum albumins which are known to be principal extracellular proteins with a high concentration in blood plasma. They act as carriers of several drugs to different molecular targets. This review summarizes the salient features of the reported work on polyphenol-protein interactions by analytical methods viz., chromatography, circular dichroism, fluorescence spectroscopy (steady state and time resolved), light scattering, equilibrium dialysis, differential scanning calorimetry, UV-vis spectroscopy, isothermal calorimetry, MALDI-TOF mass spectrometry, size exclusion chromatography, capillary electrophoresis, electrospray ionization mass spectrometry, FT-IR, molecular modelling, HPLC, NMR, cyclic voltammetry etc. Polyphenol-serum albumin interaction studies assume significance from the view point of pharmacokinetics and pharmacodynamics.

The paper offers a survey on literature data on the very wide subject concerning the interaction of a particular class of polyphenols, flavonoids, with plasma proteins. Recent developments in applying fluorescence (steady-state, time-resolved, synchronous techniques), circular dichroism and vibrational (FTIR and Raman) spectroscopies for obtaining relevant parameters (binding constant, K, number of binding sites, thermodynamic effects) are presented. Attention is paid to the modifications occurring upon the interaction process in the secondary and tertiary protein structure, as well as in the ligand conformation. In this case, we underline the significant role played by analyzing the induced dichroic signals of the ligand forced to adopt a restricted conformation in the protein pocket. In order to better understand the molecular aspects of the binding process, the differences in experimental data are discussed in terms of the structural elements of flavonoids, namely the number and position of the OH groups, the presence of methoxy and glycosidic residues and the character of the C2–C3 bond in the A ring. Some correlations of logK with parameters such as the hydrophobicity, hydrogen bond donor and acceptor character, and polar surface are also discussed. In the last section we present the representative theoretical results obtained insofar on both isolated ligands (by DFT and TDDFT methods) and supramolecular ligand–protein systems (by molecular mechanics and dynamics).

In 1936, Rusznyak and Szent-Gyorgyi first drew attention to the therapeutically beneficial role of dietary flavonoids, which are the most common group of polyphenols ubiquitously present in plant based food and beverages. Recent years have witnessed a renascence of interest on these nutraceuticals, which, because of their high potency and low systemic toxicity, are gradually emerging as promising alternatives to conventional therapeutic drugs. There is a mounting evidence that various proteins frequently serve as targets for therapeutically important flavonoids. In this article we present perspectives exemplifying the growing potential of fluorescence spectroscopy as an exquisitely sensitive tool for noninvasive sensing of protein-flavonoid interactions at physiologically relevant concentrations, via measurements of steady state emission parameters as well as decay kinetics studies of the intrinsic fluorescence of the target (protein) and/or ligand (flavonoid). Especially, we highlight novel applications of the remarkably environment sensitive ‘two color’ fluorescence exhibited by many important flavonoids, which permits multiparametric and ratiometric measurements. To consolidate findings obtained via fluorescence spectroscopy, use of other relevant experimental biophysical techniques and molecular modeling have proved to be valuable and are also discussed here. Such complementary studies provide additional insights regarding the thermodynamics and conformational aspects of the protein-flavonoid interactions, together with details, at atomistic level, of the dominant noncovalent interactions involved in the docking of different flavonoids to their target proteins.

Curcumin, a natural bioactive polyphenol, has been widely investigated as a conventional medicine for centuries. Over the past two decades, major pre-clinical and clinical trials have demonstrated its safe therapeutic profile but clinical translation has been hampered due to rapid degradation, poor water solubility, bioavailability and pharmaco-kinetics. To overcome such translational issues, many laboratories have focused on developing curcumin nanoformulations for cancer therapeutics. In this review, we discuss the evolution of curcumin nanomedicine in cancer therapeutics, the possible interactions between the surface of curcumin nanoparticles and plasma proteins, the role of nanoparticle-protein complex architecture parameters, and the rational design of clinically useful curcumin nanoformulations. Considering all the biologically relevant phenomena, curcumin nanoformulations can be developed as a new neutraceutical or pharmaceutical agent.