Effects of CYP7B1-related steroids on androgen receptor activation in different cell lines
- 作者：Johan Lundqvist1 ; Maria Norlin ; Maria.Norlin@farmbio.uu.se
- 关键词：3尾-Adiol ; 5伪-androstane-3尾 ; 17尾-diol ; Aene-diol ; 5-androstene-3尾 ; 17尾-diol ; Aene-triol ; 5-androstene-3尾 ; 7伪 ; 17尾-triol ; AR ; androgen receptor ; ARE ; androgen response element ; CYP ; cytochrome P450 ; DHEA ; dehydroepiandrosterone ; DHT ; dihydrotestosteron
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
- 出版年：2012
- 期刊代码：18_13881981
- 类别：bio
- 出版时间：July, 2012
- 卷：1821
- 期：7
- 页码：973-979
- 文件大小：566 K
摘要
The widely expressed steroid hydroxylase CYP7B1 is involved in metabolism of a number of steroids reported to influence estrogen and androgen signaling. Several studies by us and other investigators have linked this enzyme to effects on estrogen receptor activation. In a previous report we examined the effect of CYP7B1-mediated hormone metabolism for estrogen-mediated response in kidney-derived HEK293 cells. In the current study we used an androgen response element (ARE) reporter system to examine androgen-dependent response of some CYP7B1 substrates and CYP7B1-formed metabolites in several cell lines derived from different tissues. The results indicate significantly lower androgen receptor activation by CYP7B1-formed steroid metabolites than by the corresponding steroid substrates, suggesting that CYP7B1-mediated catalysis may decrease some androgenic responses. Thus, CYP7B1-dependent metabolism may be of importance not only for estrogenic signaling but also for androgenic. This finding, that CYP7B1 activity may be a regulator of androgenic signaling by converting AR ligands into less active metabolites, is also supported by real-time RT-PCR experiment where a CYP7B1 substrate, but not the corresponding product, was able to stimulate known androgen-sensitive genes. Furthermore, our data indicate that the effects of some steroids on hormone response element reporter systems are cell line-specific. For instance, despite transfection of the same reporter systems, 5-androstene-3尾,17尾-diol strongly activates an androgen-dependent response element in prostate cancer cells whereas it elicits only ER-dependent responses in kidney HEK293 cells. Potential roles of cell-specific metabolism or comodulator expression for the observed differences are discussed.