Current Drug Metabolism (v.14, #4)

Disposition of Pharmacologically Active Dietary Isoflavones in Biological Systems by Wahajuddin, Isha Taneja, Sumit Arora, Kanumuri Siva Rama Raju, Nida Siddiqui (369-380).
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 isoflavonesare increasingly being investigated as potential alternate therapies for a range of hormone-dependent conditions, including cancer, menopausalsymptoms, osteoporosis and cardiovascular diseases. However, they exhibit poor oral bioavailability which limits their clinicalutility in humans. The reason being, they are substrates of a plethora of enzymes and transporters and undergo extensive conjugative metabolismwhich facilitates their rapid elimination from biological systems. In addition, a number of experimental studies have also revealedthat these isoflavones are potent inhibitors of various cytochrome P450 isoforms and transporters which play an important role inthe disposition of many commonly prescribed drugs. Thus, there arise chances of observing clinically relevant herb-drug interactionswhich could sometimes be life-threatening. This review gives a comprehensive understanding of these dietary phytoestrogens with regardto 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/effluxtransporters and the resulting diet-drug interactions have also been discussed.

Metabolism of Dietary Flavonoids in Liver Microsomes by Jianbo Xiao, Petra Hogger (381-391).
Flavonoids undergo substantial hepatic metabolism and the metabolites might significantly contribute to the effects of thesedietary constituents. The metabolites of flavonoids in liver can be summarized as follows: 1) For flavones, the hydroxylation appears tooccur 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 positionedat 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. Flavoneglycosides 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 glucuronidationtakes place at the 7, 3, 3' and 4'- hydroxyl moiety. 3) For isoflavones, the microsomal hydroxylation is observed at the C-3'-, C-6 andC-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 whenthere 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: A Diverse Class of Multi-Target Anti-HIV-1 Agents by Kerstin Andrae-Marobela, Fotso Wabo Ghislain, Harriet Okatch, Runner R.T. Majinda (392-413).
Polyphenols are a versatile class of compounds that represent secondary metabolites from higher plants and which are abundantlypresent 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 infectionand 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 haveemerged 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 compoundclasses - exert their activities. Additionally, this review discusses polyphenols as multi-target anti-HIV agents and provides thecontext of in-vivo and clinical data. Based on the presented data, a three-pronged approach for further anti-HIV drug discovery is suggestedapplying methods of combinatorial medicinal chemistry on the diverse and sometimes unique scaffolds of polyphenols. The latterbeing selected according to the approach of 'reverse pharmacology' as a creative way to place safety and other clinical consideration atthe beginning of the drug discovery- and development process.

The properties of polyphenols as AGEs formation inhibitors have attracted great interest among researchers. This review discussesthe antiglycation activities of polyphenols and focuses on the relationship between the AGEs formation inhibitory activities andtheir chemical structures. The molecular structures influence the inhibition in the following ways: (1) The hydroxylation on both A ringand B ring improved the inhibitory activity on AGEs formation, while hydroxylation on C ring decreased the activity. (2) The methylationgenerally reduced the anti-AGEs activity of flavonoids, except for the 3-O-methylation of flavonols. (3) The glycosylation of hydroxylsof flavonoids tended to decrease the inhibitory activities on inhibiting AGEs formation, although contradictionary results wereexisted. (4) Hydrogenation of the C2=C3 double bond of flavones slightly weakened their activities. (5) A 5,7-dihydroxy structure wasfavorable to the activity of isoflavones. (6) Proanthocyanidins dimer or trimers showed a stronger inhibitory activity than catechins, andthe glucosides of anthocyanidin had higher activities than their rutinosides. (7) The hydroxylation on B ring and the methylation of stilbenesdecreased the inhibitory activity. (8) Presence of galloyl groups was important for the activity of catechins, and α-hydroxyl groupat C-3 was much more effective than β-hydroxyl group at C-3. (9) The phenolic acids with multiple hydroxyls showed strong inhibitionagainst 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 theactivities but methylation decreased them.

The plant natural products known as polyphenols are found at micronutrient levels in fruits, vegetables, and plant-based beveragessuch as wine, tea, coffee and cocoa. Consumption of a fruit- and vegetable-rich diet, the "Mediterranean diet", has been epidemiologicallyrelated 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 forpolyphenols in maintaining good health. However, molecular mechanisms for therapeutic or preventative activity have not been demonstratedin vivo. We summarize the chemical classes of natural polyphenols, their bioactivities and bioavailability and metabolism. Becausemany 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 teashow excellent antioxidant potential, which is beneficial for many diseases such as cancers and cardiovascular diseases. These Tea catechinscan 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 articleshave 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 bloodthrough hydrophobic or hydrophilic interactions. It was found that the effect of polyphenol-plasma protein interaction (PpPI) on thebioavailability of polyphenols is not equivocal. Because the conclusion of individual reports are contradictory to each other; therefore, itis very difficult to give a univocal comment on the influence of PpPI on antioxidant property of polyphenols. The influence of PpPI onthe 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.

Interactions of Polyphenols with Plasma Proteins: Insights from Analytical Techniques by Seetharamappa Jaldappagari, Sandhya Balakrishnan, Ashwini H. Hegde, Nagappa L. Teradal, Prashanth S. Narayan (456-473).
Phenolic compounds are commonly found in natural sources like plant-based foods and beverages. These compounds have receivedmuch attention due to their unique biological properties. Polyphenols possess a significant binding affinity for serum albuminswhich are known to be principal extracellular proteins with a high concentration in blood plasma. They act as carriers of several drugs todifferent molecular targets. This review summarizes the salient features of the reported work on polyphenol-protein interactions by analyticalmethods 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 pharmacokineticsand pharmacodynamics.

New Insights on Flavonoid-Serum Albumin Interactions from Concerted Spectroscopic Methods and Molecular Modeling by Sorana Ionescu, Iulia Matei, Cristina Tablet, Mihaela Hillebrand (474-490).
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 processin the secondary and tertiary protein structure, as well as in the ligand conformation. In this case, we underline the significant roleplayed by analyzing the induced dichroic signals of the ligand forced to adopt a restricted conformation in the protein pocket. In order tobetter understand the molecular aspects of the binding process, the differences in experimental data are discussed in terms of the structuralelements of flavonoids, namely the number and position of the OH groups, the presence of methoxy and glycosidic residues and thecharacter of the C2-C3 bond in the A ring. Some correlations of logK with parameters such as the hydrophobicity, hydrogen bond donorand acceptor character, and polar surface are also discussed. In the last section we present the representative theoretical results obtainedinsofar on both isolated ligands (by DFT and TDDFT methods) and supramolecular ligand-protein systems (by molecular mechanics anddynamics).

Interactions of Dietary Flavonoids with Proteins: Insights from Fluorescence Spectroscopy and Other Related Biophysical Studies by Sudip Chaudhuri, Bidisha Sengupta, Jasmine Taylor, Biswa Pathik Pahari, Pradeep K. Sengupta (491-503).
In 1936, Rusznyak and Szent-Gyorgyi first drew attention to the therapeutically beneficial role of dietary flavonoids, whichare the most common group of polyphenols ubiquitously present in plant based food and beverages. Recent years have witnessed a renascenceof interest on these nutraceuticals, which, because of their high potency and low systemic toxicity, are gradually emerging as promisingalternatives to conventional therapeutic drugs. There is a mounting evidence that various proteins frequently serve as targets fortherapeutically important flavonoids. In this article we present perspectives exemplifying the growing potential of fluorescence spectroscopyas 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' fluorescenceexhibited by many important flavonoids, which permits multiparametric and ratiometric measurements. To consolidate findings obtainedvia fluorescence spectroscopy, use of other relevant experimental biophysical techniques and molecular modeling have proved to bevaluable and are also discussed here. Such complementary studies provide additional insights regarding the thermodynamics and conformationalaspects of the protein-flavonoid interactions, together with details, at atomistic level, of the dominant noncovalent interactionsinvolved in the docking of different flavonoids to their target proteins.

Plasma Proteins Interaction with Curcumin Nanoparticles: Implications in Cancer Therapeutics by Murali M. Yallapu, Mara C. Ebeling, Meena Jaggi, Subhash C. Chauhan (504-515).
Curcumin, a natural bioactive polyphenol, has been widely investigated as a conventional medicine for centuries. Over the pasttwo decades, major pre-clinical and clinical trials have demonstrated its safe therapeutic profile but clinical translation has been hampereddue to rapid degradation, poor water solubility, bioavailability and pharmaco-kinetics. To overcome such translational issues, many laboratorieshave focused on developing curcumin nanoformulations for cancer therapeutics. In this review, we discuss the evolution of curcuminnanomedicine 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 pharmaceuticalagent.