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Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Udhane Sameer S., Dick Bernhard, Hu Qingzhong, Hartmann Rolf W., Pandey Amit V.,
Project Pathogenesis of disorders caused by human P450 oxidoreductase mutations
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Original article (peer-reviewed)

Journal Biochemical and Biophysical Research Communications
Volume (Issue) 477(4)
Page(s) 1005 - 1010
Title of proceedings Biochemical and Biophysical Research Communications
DOI 10.1016/j.bbrc.2016.07.019

Abstract

The orteronel, abiraterone and galeterone, which were developed to treat castration resistant prostate cancer, inhibit 17,20 lyase activity but little is known about their effects on adrenal androgen biosynthesis. We studied the effect of several inhibitors and found that orteronel was selective towards 17,20 lyase activity than abiraterone and galeterone. Gene expression analysis showed that galeterone altered the expression of HSD3B but orteronel did not change the expression of HSD3B, CYP17A1 and AKR1C2. The CYP19A1 activity was not inhibited except by compound IV which lowered activity by 23%. Surprisingly abiraterone caused complete blockade of CYP21A2 activity. Analysis of steroid metabolome by gas chromatography - mass spectrometry revealed changes in steroid levels caused by different inhibitors. We can conclude that orteronel is a highly specific inhibitor of 17,20 lyase activity. The discovery of these specific drug actions on steroidogenic enzyme activities would be valuable for understanding the regulation of androgens.
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