Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis

Area of Science:

• Endocrinology
• Biochemistry
• Pharmacology

Background:

• Castration-resistant prostate cancer treatments like orteronel, abiraterone, and galeterone target 17,20 lyase.
• Limited knowledge exists regarding their precise impact on adrenal androgen biosynthesis.

Purpose of the Study:

• To investigate the effects of orteronel, abiraterone, and galeterone on adrenal steroidogenic enzyme activity.
• To determine the selectivity of orteronel as a 17,20 lyase inhibitor.

Main Methods:

• Enzyme activity assays were performed for 17,20 lyase, CYP19A1, and CYP21A2.
• Gene expression analysis of HSD3B2, CYP17A1, and AKR1C3 was conducted.
• Steroid metabolome analysis utilized gas chromatography-mass spectrometry.

Main Results:

• Orteronel demonstrated higher selectivity for 17,20 lyase compared to abiraterone and galeterone.
• Galeterone affected HSD3B2 expression, while orteronel did not alter HSD3B2, CYP17A1, or AKR1C3 expression.
• Abiraterone completely inhibited CYP21A2 activity; CYP19A1 activity was largely unaffected except by compound IV.

Conclusions:

• Orteronel is confirmed as a highly specific inhibitor of 17,20 lyase activity.
• Understanding these specific drug actions on steroidogenic enzymes is crucial for androgen regulation research.
• The distinct inhibitory profiles offer insights into managing castration-resistant prostate cancer.