Modulation of pregnane X receptor- and electrophile responsive element-mediated gene expression by dietary polyphenolic compounds.
Based on animal models, dietary polyphenols are predicted to be promising chemopreventive agents in humans. Allspice, clove, and thyme extracts as well as defined dietary polyphenolic compounds were, therefore, tested for their ability to activate mechanisms related to phase 1 enzymes, i.e., the PXR-regulated CYP3A4 promoter, and phase 2 enzymes, i.e. the EpRE-regulated promoters of gastrointestinal glutathione peroxidase (GI-GPx) and heme oxygenase-1 (HO-1), examples of Nrf2-regulated genes. From the compounds tested, clove and thyme extracts as well as curcumin and resveratrol activated the PXR. PXR activation correlated with the activation of the CYP3A4 promoter in the case of thyme extract, curcumin, and resveratrol, but not in the case of clove extract. Allspice extract, EGCG, and quercetin did not activate PXR but enhanced CYP3A4 promoter activity. Thyme extract and quercetin activated the EpRE of HO-1. Both significantly activated the GI-GPx promoter, effects that depended on a functional EpRE. Resveratrol did not activate the isolated EpRE but enhanced the GI-GPx promoter activity, whereas clove extract even inhibited it. It is concluded that individual polyphenols as well as polyphenol-rich plant extracts may affect phase 1 and 2 enzyme expression by distinct mechanisms that must be elucidated, before potential health effects can reliably be predicted.
Kluth
Dirk
D
German Institute of Human Nutrition, Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
Banning
Antje
A
Paur
Ingvild
I
Blomhoff
Rune
R
Brigelius-Flohé
Regina
R
D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D019587:Dietary Supplements; D005419:Flavonoids / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000096:biosynthesis* / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D010636:Phenols / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D059808:Polyphenols; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D011794:Quercetin / Q000494:pharmacology; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D027842:Syzygium / Q000737:chemistry; D046930:Thymus Plant / Q000737:chemistry
D005419:Flavonoids; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013267:Stilbenes; D002392:Catechin; D003577:Cytochrome P-450 Enzyme System; D011794:Quercetin; C045651:epigallocatechin gallate; D005979:Glutathione Peroxidase; D051544:Cytochrome P-450 CYP3A; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C510163:CYP3A4 protein, human; D003474:Curcumin; D000077185:Resveratrol