apigenin and naringenin

In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Butyrylcholinesterase; Carbamates; Cell Line; Cell Survival; Cholinesterase Inhibitors; Copper; Dose-Response Relationship, Drug; Drug Development; Flavanones; Humans; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Rats; Structure-Activity Relationship

The 190-kDa phosphoglycoprotein multidrug resistance protein 1 (MRP1) (ABCC1) confers resistance to a broad spectrum of anticancer drugs and also actively transports certain xenobiotics with reduced glutathione (GSH) (cotransport) as well as conjugated organic anions such as leukotriene C(4) (LTC(4)). In the present study, we have investigated a series of bioflavonoids for their ability to influence different aspects of MRP1 function. Most flavonoids inhibited MRP1-mediated LTC(4) transport in membrane vesicles and inhibition by several flavonoids was enhanced by GSH. Five of the flavonoids were competitive inhibitors of LTC(4) transport (K(i), 2.4-21 microM) in the following rank order of potency: kaempferol > apigenin (+ GSH) > quercetin > myricetin > naringenin (+ GSH). These flavonoids were less effective inhibitors of 17beta-estradiol 17beta-(D-glucuronide) transport. Moreover, their rank order of inhibitory potency for this substrate differed from that for LTC(4) transport inhibition but correlated with their relative lipophilicity. Several flavonoids, especially naringenin and apigenin, markedly stimulated GSH transport by MRP1, suggesting they may be cotransported with this tripeptide. Quercetin inhibited the ATPase activity of purified reconstituted MRP1 but stimulated vanadate-induced trapping of 8-azido-alpha-[(32)P]ADP by MRP1. In contrast, kaempferol and naringenin stimulated both MRP1 ATPase activity and trapping of ADP. In intact MRP1-overexpressing cells, quercetin reduced vincristine resistance from 8.9- to 2.2-fold, whereas kaempferol and naringenin had no effect. We conclude that dietary flavonoids may modulate the organic anion and GSH transport, ATPase, and/or drug resistance-conferring properties of MRP1. However, the activity profile of the flavonoids tested differed from one another, suggesting that at least some of these compounds may interact with different sites on the MRP1 molecule.

Topics: Adenosine Diphosphate; Adenosine Triphosphatases; Antineoplastic Agents, Phytogenic; ATP-Binding Cassette Transporters; Azides; Binding, Competitive; Biological Transport; Cell Division; Chromatography, High Pressure Liquid; Drug Interactions; Estradiol; Estrogen Antagonists; Flavanones; Flavonoids; Glutathione; HeLa Cells; Humans; Kaempferols; Kinetics; Leukotriene C4; Multidrug Resistance-Associated Proteins; Phosphorus Radioisotopes; Quercetin; Transfection; Tritium; Vanadates; Vincristine

We have used a tissue culture system based on breast carcinoma cell lines to investigate a large number of naturally occurring compounds and beverages for steroid hormone agonist and antagonist activity. The cell lines used, T-47D and BT-474, produce prostate specific antigen (PSA) upon stimulation with androgens, progestins, glucocorticoids and mineralocorticoids. This biomarker is secreted and can be measured in the tissue culture supernatant with very high sensitivity by an immunofluorometric procedure. Steroid hormone antagonist activity can be assessed with the same system by adding the candidate antagonist first and then stimulating the cells with a known agonist. By using this system we have identified three natural compounds, apigenin, naringenin and syringic acid which exhibited weak progestational activity and eleven other compounds which exhibited weak antiandrogenic/antiprogestational activity. Our study indicates that a significant number of natural compounds have the ability to bind to steroid hormone receptors and act as weak blockers. A fewer number of compounds not only bind to the receptors but they also mediate transcriptional activity, acting as agonists. The agonists and antagonists were active at levels around 10(-5) M, in accordance with previous reports for other phytochemicals. In comparison to synthetic and natural steroid hormones, the biological activity of these compounds is weaker by a factor of approximately 10(4)-fold.

Topics: Beverages; Breast Neoplasms; Chamomile; Estrogen Antagonists; Female; Flavanones; Flavonoids; Fruit; Gallic Acid; Humans; Imidazoles; Mifepristone; Nitriles; Oils, Volatile; Plant Extracts; Plants, Medicinal; Prostate-Specific Antigen; Receptors, Androgen; Receptors, Progesterone; Transcription, Genetic; Tumor Cells, Cultured; Vegetables

Flavonoid and isoflavonoid glycosides are common dietary phenolics which may be absorbed from the small intestine of humans. The ability of cell-free extracts from human small intestine and liver to deglycosylate various (iso)flavonoid glycosides was investigated. Quercetin 4'-glucoside, naringenin 7-glucoside, apigenin 7-glucoside, genistein 7-glucoside and daidzein 7-glucoside were rapidly deglycosylated by both tissue extracts, whereas quercetin 3,4'-diglucoside, quercetin 3-glucoside, kaempferol 3-glucoside, quercetin 3-rhamnoglucoside and naringenin 7-rhamnoglucoside remained unchanged. The Km for hydrolysis of quercetin 4'-glucoside and genistein 7-glucoside was approximately 32+/-12 and approximately 14+/-3 microM in both tissues respectively. The enzymatic activity of the cell-free extracts exhibits similar properties to the cytosolic broad-specificity -glucosidase previously described in mammals.

Topics: beta-Glucosidase; Cell Extracts; Cell-Free System; Chamomile; Cytosol; Flavanones; Flavonoids; Genistein; Gluconates; Glycosides; Glycosylation; Humans; Inositol; Intestine, Small; Isoflavones; Lactones; Liver; Oils, Volatile; Plants, Medicinal; Quercetin; Rutin; Taurocholic Acid

Apigenin is a flavonoid that effectively blocks intercellular adhesion molecule-1 (ICAM-1) upregulation and leukocyte adhesion in response to cytokines in vitro. In the present study, we characterized the effects of tumor necrosis factor (TNF) on ICAM-1 expression in different tissues of the rat. We then assessed whether apigenin alters this response.. ICAM-1 expression was measured under baseline conditions or 5 h after treatment with rTNF. We used 125I-labeled anti-rat ICAM-1 monoclonal antibody (mAb) and an isotype-matched control mAb labeled with 131I to correct for nonspecific accumulation of the binding mAb. Animals were pretreated with either placebo, apigenin, narigenin (a flavonoid without inhibitory effect in vitro), or vehicle. Additional groups of animals were treated with either allopurinol, glutathione, dimethyl-thiourea, or an anti-CD18 monoclonal antibody in order to assess possible actions of flavonoids that were mediated via free radical scavenging or through interference with neutrophil function.. Treatment with rTNF resulted in a marked increase in ICAM-1 expression in all organs studied. The magnitude of the response varied in different organs and increases ranged from onefold (lung) to threefold (muscle). Treatment with apigenin blocked ICAM-1 upregulation in organs with low to intermediate responses to rTNF and it significantly attenuated the increased ICAM-1 expression in organs that normally exhibit more marked upregulation. Treatment with narigenin or vehicle did not affect rTNF-induced ICAM-1 upregulation in all tissues studied. Pretreatment with either allopurinol, free radical scavengers, or anti-CD18 monoclonal antibody did not affect the ICAM-1 upregulatory response to rTNF.. TNF-induced ICAM-1 upregulation in vivo effectively is blocked by apigenin through a mechanism that is unrelated to free radical scavenging or leukocyte function.

Topics: Animals; Cell Adhesion; Chamomile; Enzyme Inhibitors; Flavanones; Flavonoids; Heart; Hyaluronoglucosaminidase; Intercellular Adhesion Molecule-1; Intestinal Mucosa; Intestines; Liver; Lung; Myocardium; Oils, Volatile; Plants, Medicinal; Rats; Tumor Necrosis Factor-alpha; Up-Regulation; Xanthine Oxidase

Recent in vivo studies in humans have shown a dramatic effect of grapefruit juice in blocking the oxidation of dihydropyridine calcium channel blockers. The flavonoid naringin is the most abundant natural product specific for grapefruit and related citrus--the aglycone naringenin, known to be readily formed from naringin in humans, was found to inhibit the oxidation of the dihydropyridines nifedipine and felodipine in human liver microsomal preparations. These observations were of interest in light of the knowledge that the same human liver cytochrome P450 (IIIA4) appears to be a major catalyst in both nifedipine oxidation and aflatoxin B1 activation. Several flavones inhibited the in vitro activation of aflatoxin B1 in a system employing umuC gene activation due to DNA damage in Salmonella typhimurium TA1535/pSK1002, with naringenin being as effective as any. The high concentration of derivatives of naringenin in certain citrus fruits may be of relevance to cancer chemoprevention involving those carcinogens that are activated by cytochrome P-450IIIA4.

Topics: Aflatoxins; Chamomile; Chromatography, High Pressure Liquid; Dihydropyridines; Felodipine; Flavanones; Flavins; Flavonoids; Gene Expression Regulation; Hesperidin; Humans; In Vitro Techniques; Kaempferols; Microsomes, Liver; Oils, Volatile; Plants, Medicinal; Quercetin; Transcriptional Activation

Luteolin is a phenolic compound from plants that acts as a potent and specific inducer of nodABC gene expression in Rhizobium meliloti. We have found that R. meliloti RCR2011 exhibits positive chemotaxis towards luteolin. A maximum chemotactic response was observed at 10(-8) M. Two closely related flavonoids, naringenin and apigenin, were not chemoattractants. The presence of naringenin but not apigenin abolished chemotaxis of R. meliloti towards luteolin. A large deletion in the nif-nod region of the symbiotic megaplasmid eliminated all chemotactic response to luteolin but did not affect general chemotaxis, as indicated by swarm size on semisoft agar plates and chemotaxis towards proline in capillary tubes. Transposon Tn5 mutations in nodD, nodA, or nodC selectively abolished the chemotactic response of R. meliloti to luteolin. Agrobacterium tumefaciens GMI9050, a derivative of the C58 wild type lacking a Ti plasmid, responded chemotactically to 10(-8) M luteolin. The introduction of a 290-kilobase nif-nod-containing sequence of DNA from R. meliloti into A. tumefaciens GMI9050 enabled the recipient to respond to luteolin at concentrations peaking at 10(-6) M as well as at concentrations peaking at 10(-8) M. The response of A. tumefaciens GMI9050 to luteolin was also abolished by the presence of naringenin.

Topics: Chamomile; Chemotaxis; Fabaceae; Flavanones; Flavonoids; Gene Expression Regulation; Genes, Bacterial; Kinetics; Luteolin; Oils, Volatile; Plant Extracts; Plants, Medicinal; Rhizobium; Symbiosis