chrysin and acacetin

Flavonoids are natural compounds that have been extensively studied due to their positive effects on human health. There are over 4000 flavonoids found in higher plants and their beneficial effects have been shown in vitro as well as in vivo. However, data on their pharmacokinetics and influence on metabolic enzymes is scarce. The aim of this study was to focus on possible interactions between the 30 most commonly encountered flavonoid aglycones on the metabolic activity of CYP3A4 enzyme. 6β-hydroxylation of testosterone was used as marker reaction of CYP3A4 activity. Generated product was determined by HPLC coupled with diode array detector. Metabolism and time dependence, as well as direct inhibition, were tested to determine if inhibition was reversible and/or irreversible. Out of the 30 flavonoids tested, 7 significantly inhibited CYP3A4, most prominent being acacetin that inhibited 95% of enzyme activity at 1 µM concentration. Apigenin showed reversible inhibition, acacetin, and chrysin showed combined irreversible and reversible inhibition while chrysin dimethylether, isorhamnetin, pinocembrin, and tangeretin showed pure irreversible inhibition. These results alert on possible flavonoid⁻drug interactions on the level of CYP3A4.

Topics: Apigenin; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Flavanones; Flavones; Flavonoids; Humans; Quercetin; Testosterone

As a continuous effort to find new natural products with potential herbicide activity, flavonoids acacetin (1), chrysin (2) and 4',7-dimethylnarangenin (3) were isolated from a propolis sample collected in the rural area of Mexico City and their effects on the photosynthesis light reactions and on the growth of Lolium perenne, Echinochloa crus-galli and Physalis ixocarpa seedlings were investigated. Acacetin (1) acted as an uncoupler by enhancing the electron transport under basal and phosphorylating conditions and the Mg(2+)-ATPase. Chrysin (2) at low concentrations behaved as an uncoupler and at concentrations up to 100 μM its behavior was as a Hill reaction inhibitor. Finally, 4',7-dimethylnarangenin (3) in a concentration-dependent manner behaved as a Hill reaction inhibitor. Flavonoids 2 and 3 inhibited the uncoupled photosystem II reaction measured from water to 2,5-dichloro-1,4-benzoquinone (DCBQ), and they did not inhibit the uncoupled partial reactions measured from water to sodium silicomolybdate (SiMo) and from diphenylcarbazide (DPC) to diclorophenol indophenol (DCPIP). These results indicated that chrysin and 4',7-dimethylnarangenin inhibited the acceptor side of PS II. The results were corroborated with fluorescence of chlorophyll a measurements. Flavonoids also showed activity on the growth of seedlings of Lolium perenne and Echinochloa crus-galli.

Topics: Arginine; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Echinochloa; Flavones; Flavonoids; Herbicides; Lolium; Magnetic Resonance Spectroscopy; Mexico; Photosynthesis; Photosystem II Protein Complex; Physalis; Propolis; Seedlings; Spinacia oleracea

Expression level of Tumor Necrosis Factor-related apoptosis-inducing ligand (TRAIL) receptors is one of the most important factors of TRAIL-mediated apoptosis in cancer cells. We here report for the first time data concerning TRAIL-R1 and TRAIL-R2 receptor expression on RAW264.7 macrophages. Three substances belonging to flavones: chrysin, apigenin and acacetin which differ from their substituents at the 4' position in the phenyl ring were used in assays because of the variety of biological activities (e.g., anticancer activity) of the polyphenol compounds. The expression of TRAIL-R1 and TRAIL-R2 death receptors on non-stimulated and LPS (lipopolysaccharide)-stimulated macrophages was determined using flow cytometry. We demonstrate that RAW264.7 macrophages exhibit TRAIL-R1 surface expression and that the tested compounds: chrysin, apigenin and acacetin can inhibit TRAIL-R1 death receptor expression level on macrophages.

Topics: Animals; Apigenin; Cell Line; Flavones; Flavonoids; Macrophages; Mice; Receptors, TNF-Related Apoptosis-Inducing Ligand

CYP1A1 and CYP1B1 are two extrahepatic enzymes that have been implicated in carcinogenesis and cancer progression. Selective inhibition of CYP1A1 and CYP1B1 by dietary constituents, notably the class of flavonoids, is a widely accepted paradigm that supports the concept of dietary chemoprevention. In parallel, recent studies have documented the ability of CYP1 enzymes to selectively metabolize dietary flavonoids to conversion products that inhibit cancer cell proliferation. In the present study we have examined the inhibition of CYP1A1 and CYP1B1-catalyzed EROD activity by 14 different flavonoids containing methoxy- and hydroxyl-group substitutions as well as the metabolism of the monomethoxylated CYP1-flavonoid inhibitor acacetin and the poly-methoxylated flavone eupatorin-5-methyl ether by recombinant CYP1A1 and CYP1B1. The most potent inhibitors of CYP1-EROD activity were the methoxylated flavones acacetin, diosmetin, eupatorin and the di-hydroxylated flavone chrysin, indicating that the 4'-OCH(3) group at the B ring and the 5,7-dihydroxy motif at the A ring play a prominent role in EROD inhibition. Potent inhibition of CYP1B1 EROD activity was also obtained for the poly-hydroxylated flavonols quercetin and myricetin. HPLC metabolism of acacetin by CYP1A1 and CYP1B1 revealed the formation of the structurally similar flavone apigenin by demethylation at the 4'-position of the B ring, whereas the flavone eupatorin-5-methyl ether was metabolized to an as yet unidentified metabolite assigned E(5)M1. Eupatorin-5-methyl ether demonstrated a submicromolar IC(50) in the CYP1-expressing cancer cell line MDA-MB 468, while it was considerably inactive in the normal cell line MCF-10A. Homology modeling in conjunction with molecular docking calculations were employed in an effort to rationalize the activity of these flavonoids based on their CYP1-binding mode. Taken together the data suggest that dietary flavonoids exhibit three distinct modes of action with regard to cancer prevention, based on their hydroxyl and methoxy decoration: (1) inhibitors of CYP1 enzymatic activity, (2) CYP1 substrates and (3) substrates and inhibitors of CYP1 enzymes.

Topics: Aryl Hydrocarbon Hydroxylases; Binding Sites; Cell Line; Computer Simulation; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Enzyme Inhibitors; Flavones; Flavonoids; Humans; Recombinant Proteins; Substrate Specificity

The effect of five propolis flavonoids on the infectivity and replication of some herpesvirus, adenovirus, coronavirus and rotavirus strains has been studied. Experiments were performed in vitro in cell cultures using the viral plaque reduction technique. The cytotoxicity of flavonoids, including chrysine, kaempferol, acacetin, galangin and quercetin, was evaluated on uninfected monolayers to determine their effect on cell growth and viability. Chrysine and kaempferol caused a concentration-dependent reduction of intracellular replication of herpes-virus strains when monolayers were infected and subsequently cultured in a drug-containing medium. However, virus infectivity was not significantly affected. Acacetin and galangin had no effect on either the infectivity or replication of any of the viruses studied. Quercetin reduced infectivity and intracellular replication, but only at the highest concentrations tested.

Topics: Animals; Cell Line; Flavones; Flavonoids; Humans; Immunoenzyme Techniques; Kaempferols; Molecular Structure; Quercetin; Vero Cells; Viral Plaque Assay; Virus Replication; Viruses