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2963710 
Journal Article 
Dual action of oestrogens on the mouse constitutive androstane receptor 
Mäkinen, J; Reinisalo, M; Niemi, K; Viitala, P; Jyrkkärinne, J; Chung, H; Pelkonen, O; Honkakoski, P 
2003 
Yes 
Biochemical Journal
ISSN: 0264-6021
EISSN: 1470-8728 
376 
Pt 2 
465-472 
English 
12948398 
WOS:000187250000016 
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. 
co-activator; co-repressor; HEK-293 cells; hepatocyte; nuclear receptor CAR (constitutive androstane receptor); oestrogen