chrysin and catechin-gallate

The constitutive androstane receptor (CAR) is known as a xeno-sensor that regulates genes involved in xenobiotic excretion and energy metabolism. This study tested a variety of polyphenols for their ability to modulate CAR activity. HepG2 cells were transfected with a CAR expression plasmid and a reporter plasmid containing the human CYP2B6 regulatory region and then treated with flavonoids, catechins, and other bioactive polyphenols. Luciferase assays revealed that baicalein (5,6,7-OH flavone) was a potent activator of both human and mouse CAR. Catechin gallates also activated human and mouse CAR. Wild-type and CAR knockout mice were treated with baicalein and chrysin (5,7-OH flavone), and their liver mRNA was analyzed by real-time polymerase chain reaction (PCR). A significant increase in cyp2b10 mRNA content was observed only in wild-type mice fed chrysin. These results suggest that dietary flavonoids regulate CAR activity and thereby accelerate both detoxification and energy metabolism.

Topics: Androstanes; Animals; Aryl Hydrocarbon Hydroxylases; Carcinoma, Hepatocellular; Catechin; Cell Line, Tumor; Constitutive Androstane Receptor; Cytochrome P450 Family 2; Diet; Flavonoids; Genes, Reporter; Humans; Liver; Liver Neoplasms; Luciferases; Mice; Mice, Knockout; Polymerase Chain Reaction; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Steroid Hydroxylases

After the discovery of a potent natural flavonoid glucoside as a potent inhibitor of FabI, a large flavonoid library was screened against three important enzymes (i.e., FabG, FabZ, and FabI) involved in the fatty acid biosynthesis of P. falciparum. Although flavones with a simple hydroxylation pattern (compounds 4-9) showed moderate inhibitory activity toward the enzymes tested (IC50 10-100 microM), the more complex flavonoids (12-16) exhibited strong activity toward all three enzymes (IC50 0.5-8 microM). Isoflavonoids 26-28 showed moderate (IC50 7-30 microM) but selective activity against FabZ. The most active compounds were C-3 gallic acid esters of catechins (32, 33, 37, 38), which are strong inhibitors of all three enzymes (IC50 0.2-1.1 microM). Kinetic analysis using luteolin (12) and (-)-catechin gallate (37) as model compounds revealed that FabG was inhibited in a noncompetitive manner. FabZ was inhibited competitively, whereas both compounds behaved as tight-binding noncompetitive inhibitors of FabI. In addition, these polyphenols showed in vitro activity against chloroquine-sensitive (NF54) and -resistant (K1) P. falciparum strains in the low to submicromolar range.

Topics: 3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; Alcohol Oxidoreductases; Animals; Antimalarials; Catechin; Cells, Cultured; Chloroquine; Drug Resistance; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); Fatty Acids; Flavones; Flavonoids; Humans; Hydro-Lyases; Kinetics; Luteolin; Phenols; Plasmodium falciparum; Polyphenols; Structure-Activity Relationship