Activation of pregnane X receptor and induction of MDR1 by dietary phytochemicals.
The pregnane X receptor (PXR) is understood to be the key regulator for gene expression of such drug-metabolizing enzymes and transporters as multidrug-resistant protein 1 (MDR1) and the cytochrome P450 (CYP) family. We examined the effect of dietary phytochemicals on the PXR-dependent transcriptional activity in human intestinal LS180 cells by using a reporter assay. Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals. Furthermore, an increase was observed of the MDR1 protein and its functional activity by tangeretin and by ginkgolides A and B. These findings strongly suggest that tangeretin and ginkgolides A and B activated PXR, thereby regulating detoxification enzymes and transporters in the intestines.
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan. asatsu@mail.ecc.u-tokyo.ac.jp
Hideo
H
Satsu
Yuto
Y
Hiura
Keiichi
K
Mochizuki
Mika
M
Hamada
Makoto
M
Shimizu
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004032:Diet; D019587:Dietary Supplements / Q000032:analysis*; D047309:Flavones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D046934:Ginkgolides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D010936:Plant Extracts / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001688:Biological Products; D047309:Flavones; D046934:Ginkgolides; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C059006:tangeretin