ESPE Abstracts (2015) 84 P-1-4

Effect of CYP17A1 Inhibitors Orteronel and Galeterone on Adrenal Androgen Biosynthesis

Sameer S Udhane & Amit V Pandey


Pediatric Endocrinology and Diabetology, Department of Pediatrics, University Children’s Hospital, Inselpital, Bern, Switzerland


Background: The cytochrome P450 CYP17A1 plays a vital role in regulating adrenal androgen production. The 17,20 lyase activity of CYP17A1 is key for androgen regulation. The orteronel and galeterone are known to inhibit 17,20 lyase activity however the detailed mechanisms of the inhibition of CYP17A1 activities remain unknown. These inhibitors have been developed to treat the castration resistant prostate cancer (CRPC) but little is known about their effects on adrenal androgen biosynthesis.

Objective and hypotheses: The objective of this study is to study the effect of inhibitors on CYP17A1 enzyme activity and adrenal androgen biosynthesis.

Method: We used NCI-H295R adenocarcinoma cell model to study the effect of orteronel and galeterone. We treated the H295R cells at 0–2 μM orteronel and galeterone for 24 h. Steroid production was labeled with [3H] pregnenolone for 90 min. Steroids were extracted and resolved by thin layer chromatography. For specific analysis of the P450c17 activities, cells were treated with 1 μM trilostane (a specific blocker of HSD3B) before adding [3H] pregnenolone.

Results: The drugs orteronel and galeterone were able to inhibit CYP17A1 activity in H295R cells. Both drugs have more potency towards the 17,20 lyase activity but we also observed that they partially affected 17α-hydroxylase activity. From our results, we observed that orteronel seems to be more potent and selective towards 17,20 lyase activity than galeterone. However, we also found that DHEA, cortisol, and androstenedione were drastically decreased by both compounds at 1 and 2 μm concentration.

Conclusion: Based on these results we can conclude that orteronel is a more potent inhibitor of 17,20 lyase activity and also has partial effect on 17α-hydroxylase activities. Detailed mechanisms that alter the CYP17A1 enzyme activities need further investigation. The discovery of these drug actions on CYP17A1 activity would be of great clinical value for understanding adrenal androgen regulation.

Funding: Swiss National Science Foundation (grant number 31300-134926).

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