A bypass gateway from cholesterol to sex steroid biosynthesis circumnavigates CYP17A1.
Summary
This study uncovers a CYP51A1-driven pathway that converts an oxysterol to androgens, effectively bypassing CYP17A1. Screening of 57 human P450s and stable isotope tracing establish CYP51A1 as uniquely capable and essential for this bypass, providing a mechanism for persistent androgen biosynthesis during CYP17A1 inhibition in prostate cancer.
Key Findings
- Identified a CYP51A1-mediated route converting an oxysterol to androgens, bypassing CYP17A1.
- Among 57 human P450s tested, only CYP51A1 could circumvent CYP17A1.
- Deuterium-labeled oxysterol tracing confirmed precursor flux to androgens via the bypass.
- Stable isotope genetic tracing demonstrated CYP51A1 is essential for this biosynthetic route.
Clinical Implications
May inform biomarker development (oxysterol intermediates, CYP51A1 activity) and combination strategies to overcome abiraterone or other CYP17A1 inhibitor resistance in prostate cancer.
Why It Matters
This represents a paradigm shift in steroidogenesis and explains resistance to CYP17A1 inhibitors; it opens new therapeutic targets for endocrine-oncology.
Limitations
- Predominantly preclinical mechanistic work with limited in vivo clinical validation.
- Physiologic relevance and regulation of the pathway across tissues remain to be defined.
Future Directions
Define tissue distribution and regulation of the CYP51 bypass in humans; evaluate therapeutic inhibition of CYP51A1 in CYP17A1-inhibitor–resistant prostate cancer; develop circulating biomarkers for pathway activity.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology
- Evidence Level
- III - Well-conducted mechanistic laboratory research with multiple validation approaches
- Study Design
- OTHER