In vivo activation of the constitutive androstane receptor β (CARβ) by treatment with dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEA-S)

• Published in: FEBS letters Vol. 532; no. 3; pp. 373 - 378
• Main Authors: Fujita, Atsushi, Furutama, Daisuke, Tanaka, Toshifumi, Sakai, Reiko, Koyama, Akio, Hanafusa, Toshiaki, Mitsuhashi, Tomoaki, Ohsawa, Nakaaki
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 18.12.2002
• Subjects: Adjuvants, Immunologic - pharmacology; Animals; Blotting, Western; Cell Division; Cell Nucleus - metabolism; Constitutive androstane receptor β; Cyp2b10; Dehydroepiandrosterone; Dehydroepiandrosterone - blood; Dehydroepiandrosterone - pharmacology; Dehydroepiandrosterone Sulfate - blood; Dehydroepiandrosterone Sulfate - pharmacology; Dehydroepiandrosterone-sulfate; Dose-Response Relationship, Drug; Enzyme Activation; Ligands; Liver - metabolism; Male; Mice; Protein Binding; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Retinoic Acid - metabolism; Retinoid X receptor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Transcription Factors - metabolism; Dehydroepiandrosterone; Constitutive androstane receptor β; Retinoid X receptor; Dehydroepiandrosterone-sulfate; Cyp2b10
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(02)03712-2

We investigated whether dehydroepiandrosterone (DHEA) or DHEA-sulfate (S) affected the activities of nuclear receptors, with special reference to constitutive androstane receptor β (CARβ). Administration of DHEA or DHEA-S enhanced the DNA binding of hepatic nuclear extracts to responsive elements for the retinoic acid receptor, the retinoic acid receptor β 2 and the peroxisome proliferator activated receptor. The bound complexes were shown to be the CARβ-RXR heterodimer by antibody-supershift assays. The expression of a target gene of CARβ, Cyp2b10, was increased in liver by DHEA or DHEA-S treatment, suggesting that DHEA or DHEA-S actually activated CARβ in vivo. It was suggested that the metabolic conversion of DHEA, DHEA-S to CARβ ligands could occur in vivo and the metabolites could regulate the expression of CARβ target gene expression. Our results provide new insights into the in vivo relationship between DHEA/DHEA-S and CARβ activation.