title: Effects of CYP7B1-related steroids on androgen receptor activation in different cell lines.
abstract: 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-3β,17β-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.
authors.affiliation: Department of Pharmaceutical Biosciences, Box 591, Uppsala University, SE-751 24 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lundqvist
authors.forename: Maria
authors.initials: M
authors.lastname: Norlin
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D015114:Androstenediol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000072474:Cytochrome P450 Family 7; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009928:Organ Specificity; D011471:Prostatic Neoplasms; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000096:biosynthesis; D014162:Transfection
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D013739:Testosterone; D015114:Androstenediol; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human