title: Vitamin D Receptor-Mediated Upregulation of CYP3A4 and MDR1 by Quercetin in Caco-2 cells.
abstract: To examine whether quercetin interacts with vitamin D receptor, we investigated the effects of quercetin on vitamin D receptor activity in human intestinal Caco-2 cells. The effects of quercetin on the expression of the vitamin D receptor target genes, vitamin D3 24-hydroxylase, cytochrome P450 3A4, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were measured using quantitative polymerase chain reaction. The vitamin D receptor siRNA was used to assess the involvement of the vitamin D receptor. Vitamin D receptor activation using a vitamin D responsive element-mediated cytochrome P450 3A4 reporter gene assay was investigated in Caco-2 cells transfected with human vitamin D receptor. We also studied the magnitude of the vitamin D receptor activation and/or synergism between 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] and quercetin-like flavonoids. Slight but significant increases in the mRNA expression of cytochrome P450 3A4, vitamin D3 24-hydroxylase, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were observed after 3 days of continual quercetin treatment. The silencing effect of vitamin D receptor by vitamin D receptor siRNA in Caco-2 cells significantly attenuated the induction of the vitamin D receptor target genes. Moreover, quercetin significantly enhanced cytochrome P450 3A4 reporter activity in Caco-2 cells in a dose-dependent manner, and the expression of exogenous vitamin D receptor further stimulated the vitamin D receptor activity. Quercetin-like flavonoids such as kaempferol stimulated the vitamin D receptor activity in a manner similar to that seen with quercetin. Taken together, the data indicates that quercetin upregulates cytochrome P450 3A4 and multidrug resistance protein 1 expression in Caco-2 cells likely via a vitamin D receptor-dependent pathway.
authors.affiliation: Chong Kun Dang Research Institute, CKD Pharmaceuticals Inc., Jung-dong, Giheung, Yongin, Gyeonggi, Republic of Korea.
authors.forename: Yoon-Jee
authors.initials: YJ
authors.lastname: Chae
authors.affiliation: College of Pharmacy, Inje University, Obang-dong, Gimhae, Gyeongnam, Republic of Korea.
authors.forename: Kwan Hyung
authors.initials: KH
authors.lastname: Cho
authors.affiliation: College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, Republic of Korea.
authors.forename: In-Soo
authors.initials: IS
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Chi-Kyoung
authors.initials: CK
authors.lastname: Noh
authors.affiliation: College of Pharmacy, Inje University, Obang-dong, Gimhae, Gyeongnam, Republic of Korea.
authors.forename: Hyo-Jong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Inje University, Obang-dong, Gimhae, Gyeongnam, Republic of Korea.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Park
authors.affiliation: College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Ji
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Kyeonggi, Republic of Korea.
authors.forename: Min-Duk
authors.initials: MD
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea.
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018167:Receptors, Calcitriol; D011794:Quercetin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human