title: Dual action of oestrogens on the mouse constitutive androstane receptor.
abstract: mCAR (mouse constitutive androstane receptor; NR1I3) controls the expression of cytochrome P450 as well as other enzymes involved in drug and steroid metabolism. The high basal activity of mCAR can be modulated by inhibitory steroids related to androstenol and by activating xenobiotic chemicals such as 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene and chlorpromazine. The ability of oestrogens and some other xenobiotics to activate mCAR is not clear. In the present study, co-transfection assays in HEK-293 cells indicated that oestrogens varied in their efficacy to activate mCAR, depending on variation at the steroid D-ring and position of hydroxy groups. In general, oestrogens were weaker activators of mCAR than 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene and chlorpromazine. Also, the induction of CYP2B10 mRNA by oestrogens was less pronounced in mouse primary hepatocytes. Yeast two-hybrid assays indicated that, unlike androstenol and the established activators, oestrogens attracted both nuclear receptor co-repressors and co-activators to the mCAR ligand-binding domain, thus limiting the extent of mCAR activation. This novel dual action is not limited to oestrogens, but is shared by some xenobiotic CYP2B inducers such as clotrimazole and methoxychlor. These findings offer an alternative explanation for the recently suggested nuclear activation step of mCAR.
authors.affiliation: Department of Pharmaceutics, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Mäkinen
authors.forename: Mika
authors.initials: M
authors.lastname: Reinisalo
authors.forename: Kaisa
authors.initials: K
authors.lastname: Niemi
authors.forename: Pirkko
authors.initials: P
authors.lastname: Viitala
authors.forename: Johanna
authors.initials: J
authors.lastname: Jyrkkärinne
authors.forename: Hinfan
authors.initials: H
authors.lastname: Chung
authors.forename: Olavi
authors.initials: O
authors.lastname: Pelkonen
authors.forename: Paavo
authors.initials: P
authors.lastname: Honkakoski
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D000090702:Constitutive Androstane Receptor; D000072467:Cytochrome P450 Family 2; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000737:chemistry / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008024:Ligands; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015262:Xenobiotics / Q000494:pharmacology
chemical_list: D000090702:Constitutive Androstane Receptor; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D014157:Transcription Factors; D015262:Xenobiotics; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2