CYP17A1 inhibitor abiraterone, an anti-prostate cancer drug, also inhibits the 21-hydroxylase activity of CYP21A2.

Abstract

Abiraterone is an inhibitor of CYP17A1 which is used for the treatment of castration resistant prostate cancer. Abiraterone is known to inhibit several drug metabolizing cytochrome P450 enzymes including CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5, but its effects on steroid metabolizing P450 enzymes are not clear. In preliminary results, we had observed inhibition of CYP21A2 by 1μM abiraterone. Here we are reporting the effect of abiraterone on activities of CYP21A2 in human adrenal cells as well as with purified recombinant CYP21A2. Cells were treated with varying concentrations of abiraterone for 24h and CYP21A2 activity was measured using [3H] 17-hydroxyprogesterone as substrate. Whole steroid profile changes were determined by gas chromatography-mass spectrometry. Binding of abiraterone to purified CYP21A2 protein was measured spectroscopically. Computational docking was used to study the binding and interaction of abiraterone with CYP21A2. Abiraterone caused significant reduction in CYP21A2 activity in assays with cells and an inhibition of CYP21A2 activity was also observed in experiments using recombinant purified proteins. Abiraterone binds to CYP21A2 with an estimated Kd of 6.3μM. These inhibitory effects of abiraterone are at clinically used concentrations. A loss of CYP21A2 activity in combination with reduction of CYP17A1 activities by abiraterone could result in lower cortisol levels and may require monitoring for any potential adverse effects.

• Authors: Jana Malikova, Simone Brixius-Anderko, Sameer S Udhane, Shaheena Parween, Bernhard Dick, Rita Bernhardt, Amit V Pandey
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 174 Pg. 192-200 (11 2017) ISSN: 1879-1220 [Electronic] England
• PMID: 28893623 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Androstenes
• Antineoplastic Agents
• Steroids
• CYP21A2 protein, human
• Steroid 21-Hydroxylase
• CYP17A1 protein, human
• Steroid 17-alpha-Hydroxylase
• abiraterone

Topics

• Androstenes (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Escherichia coli (genetics)
• Humans
• Male
• Molecular Docking Simulation
• Prostatic Neoplasms
• Steroid 17-alpha-Hydroxylase (antagonists & inhibitors)
• Steroid 21-Hydroxylase (antagonists & inhibitors, chemistry, genetics, metabolism)
• Steroids (metabolism)