API

Relationship: 1878

Title

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Inhibition of Cyp17A1 activity leads to Reduction, DHEA

Upstream event

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Inhibition of Cyp17A1 activity

Downstream event

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Reduction, DHEA

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Cyp17a1 catalyzes the conversion of 17-OH-pregnenolone in DHEA through its 17α-hydroxylase activity. DHEA is synthesized by the cleavage of the c17,20 bond of 17-OH-pregnenolone. A lack in Cyp17a1’s activity directly affect this process resulting in a reduction in DHEA levels Cyp17a1 is found mainly found in Leydig cells and in the zona fasciculata/zona reticularis of the adrenal cortex.  123

Evidence Supporting this KER

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Biological Plausibility

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The biological role of Cyp17a1 in 17-OH-pregnenolone/DHEA conversion is very well established. Cyp17a1 is known to cleave the c17,20bond of 10-OH-pregnenolone through its 17α-hydroxylase activity. 123

Empirical Evidence

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A major empirical evidence came from CYP17 knock down cell studies. In 2005, Liu Y., Yao ZX., and Papadopoulos V. showed that MA-10 CYP17 knock down cells synthesize much less pregnenolone and DHEA compared with MA-10 wild type cells. In this study, de novo endogenous cholesterol synthesis was blocked with the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin. After cells incubation with a radiolabeled cholesterol precursor ([3H]mevalonactone), progesterone and DHEA were fractionned using HPLC and identify using standards. After quantification by liquid scintillation spectrometry, results indicated that the MA-10CYP17KD cells synthesize much less pregnenolone, progesterone and DHEA. These results enable to highlight the important factor of CYP17a1 in 17-OH-pregnenolone conversion to DHEA. 4

Uncertainties and Inconsistencies

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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

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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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 Auchus R.J. (2004) Overview of dehydroepiandrosterone biosynthesis. Seminars in Reproductive Medicine, 22(4):281-8.https://doi.org/10.1055/s-2004-861545 

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