Relationship: 1879
Title
Upstream event
Inhibition of Cyp17A1 activityDownstream event
Reduction, androstenedione
Key Event Relationship Overview
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding |
|---|---|---|---|
| Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals) | adjacent | High |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
Cyp17a1 catalyzes the cleavage of c17,20 bond of 17-OH-progesterone to give androstenedione. This pathway is a direct conversion of DHEA by the enzyme 3β-hydroxysteroid dehydrogenase. A diminution in Cyp17a1 activity leads to a reduction in both 17-OH-progesterone/androstenedione and DHEA/androstenedione conversion. 123
Evidence Supporting this KER
Biological Plausibility
The biological role of Cyp17a1 in 17-OH-progesterone/androstenedione conversion is very well known. Most of androstenedione is synthesized through the 17,20-lyase activity of Cyp17a1. 123
Empirical Evidence
Using MA-10 CYP17 knock down cells, Liu Y., Yao ZX., and Papadopoulos V. showed that cells without CYP17 enzyme tend to synthesize less progesterone than MA-10 wild type cells. For this particular study, endogenous cholesterol synthesis was blocked using 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin. Cells were incubated with a radioactive cholesterol precursor to allow steroidogenesis monitoring. Newly-synthesized steroids were then collected, separated and identified using HPLC. After quantification by liquid scintillation spectrometry, results indicated that the MA-10CYP17KD cells synthesize much less progesterone than wild type cells. These results enable to highlight the important factor of CYP17a1 in 17-OH-progesterone conversion in androstenedione 4
Uncertainties and Inconsistencies
The mentioned study is based on MA-10 mouse tumor Leydig cells. Even though mouse is the prefered animal model for reproductive studies, a human-cell based study would be stronger.
Quantitative Understanding of the Linkage
Domain of Applicability
References
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1 Miller Walter L. (1988) Molecular Biology of Steroid Hormone Synthesis. Endocrine Reviews, 9(3): 295-318. https://doi.org/10.1210/edrv-9-3-295 2 Miller W.L. and Auchus R.J. (2011) The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocrine Reviews, 32(1): 81-151.https://doi.org/10.1210/er.2010-0013 3 Liu Y., Yao ZX., and Papadopoulos V. (2005) Cytochrome P450 17α Hydroxylase/17,20 Lyase (CYP17) Function in Cholesterol Biosynthesis: Identification of Squalene Monooxygenase (Epoxidase) Activity Associated with CYP17 in Leydig Cells. Molecular Endocrinology, 19(7): 1918-1931 https://doi.org/10.1210/me.2004-0271 |