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Relationship: 1878
Title
Inhibition of Cyp17A1 activity leads to Reduction, DHEA
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals) | adjacent | High | Bérénice COLLET (send email) | Open for citation & comment |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
mammals | mammals | High | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Mixed | High |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | High |
Key Event Relationship Description
This key event relationship (KER) links inhibition of CYP17A1 activity to decreased dehydroepiandrosterone (DHEA) levels.
CYP17A1 plays a dual role in DHEA synthesis, as is performs both a 17α-hydroxylation and 17,20-lyase transformation. This leads to the transformation of pregnenolone to 17-OH-pregnenolone and 17-OH-pregnenolone to DHEA, respectively (Burris-Hiday & Scott, 2021; Miller & Auchus, 2011, 2019; Peng et al., 2019; Wróbel et al., 2023). If either of these reactions are inhibited, it can lead to decreased DHEA levels.
Evidence Collection Strategy
The KER describes a generally recognized and understood process, i.e. canonical knowledge. The aim of the literature search was therefore to identify review articles and book chapters that summarise
the canonical knowledge. PubMed was searched using key words related to steroidogenesis. The search was restricted to reviews from the last 10 years.
Evidence Supporting this KER
Biological Plausibility
The biological plausibility of this KER is considered high.
The CYP17A1 enzyme facilitates two reactions in the process of DHEA synthesis. A 17α-hydroxylase reaction that converts pregnenolone to 17-OH-pregnenolone and a 17,20-lyase reaction that converts 17-OH-pregnenolone to DHEA. The 17α-hydroxylase reactions take place at the C17 of pregnenolone, whereas the lyase reaction leads to a breakage between the C17 and C20 of 17-OH-pregnenolone. Both reactions are dependent on the cofactor P450 oxidoreductase, where the lyase reaction is also dependent on the cofactor cytochrome B5 (Burris-Hiday & Scott, 2021; Miller & Auchus, 2011, 2019; Peng et al., 2019; Wróbel et al., 2023).
CYP17A1 is expressed in the testis, ovary, adrenal, but also in the placenta, heart, adipose, liver, brain, and kidney tissue depending on species (Zirkin & Papadopoulos, 2018). Specifically, CYP17A1 is expressed in the testicular Leydig cells, in the ovarian Theca cells and in the zona reticularis and zona fasciculate of the adrenal gland (Chatuphonprasert et al., 2018; Odermatt et al., 2016; Peng et al., 2019; Petrunak et al., 2014; Storbeck et al., 2011; Wróbel et al., 2023).
The lyase reaction leading to DHEA from 17-OH-pregnenolone is dominant in humans and primates compared to rodents (Lawrence et al., 2022; Miller & Auchus, 2011).
Empirical Evidence
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.
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.
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This KE is applicable for both sexes, across developmental stages into adulthood, and across mammalian taxa.
References
Burris-Hiday, S. D., & Scott, E. E. (2021). Steroidogenic cytochrome P450 17A1 structure and function. Molecular and Cellular Endocrinology, 528. https://doi.org/10.1016/j.mce.2021.111261
Chatuphonprasert, W., Jarukamjorn, K., & Ellinger, I. (2018). Physiology and pathophysiology of steroid biosynthesis, transport and metabolism in the human placenta. In Frontiers in Pharmacology (Vol. 9, Issue SEP). Frontiers Media S.A. https://doi.org/10.3389/fphar.2018.01027
Lawrence, B. M., O’Donnell, L., Smith, L. B., & Rebourcet, D. (2022). New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice. In International Journal of Molecular Sciences (Vol. 23, Issue 24). MDPI. https://doi.org/10.3390/ijms232415555 Miller, W. L., & 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
Miller, W. L., & Auchus, R. J. (2019). The “backdoor pathway” of androgen synthesis in human male sexual development. PLoS Biology, 17(4). https://doi.org/10.1371/journal.pbio.3000198
Odermatt, A., Strajhar, P., & Engeli, R. T. (2016). Disruption of steroidogenesis: Cell models for mechanistic investigations and as screening tools. In Journal of Steroid Biochemistry and Molecular Biology (Vol. 158, pp. 9–21). Elsevier Ltd. https://doi.org/10.1016/j.jsbmb.2016.01.009
Peng, Z., Xueb, G., Chen, W., & Xia, S. (2019). Environmental inhibitors of the expression of cytochrome P450 17A1 in mammals. In Environmental Toxicology and Pharmacology (Vol. 69, pp. 16–25). Elsevier B.V. https://doi.org/10.1016/j.etap.2019.02.007
Petrunak, E. M., DeVore, N. M., Porubsky, P. R., & Scott, E. E. (2014). Structures of human steroidogenic cytochrome P450 17A1 with substrates. Journal of Biological Chemistry, 289(47), 32952–32964. https://doi.org/10.1074/jbc.M114.610998
Storbeck, K. H., Swart, P., Africander, D., Conradie, R., Louw, R., & Swart, A. C. (2011). 16α-Hydroxyprogesterone: Origin, biosynthesis and receptor interaction. In Molecular and Cellular Endocrinology (Vol. 336, Issues 1–2, pp. 92–101). https://doi.org/10.1016/j.mce.2010.11.016
Wróbel, T. M., Jørgensen, F. S., Pandey, A. V., Grudzińska, A., Sharma, K., Yakubu, J., & Björkling, F. (2023). Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment. In Journal of Medicinal Chemistry (Vol. 66, Issue 10, pp. 6542–6566). American Chemical Society. https://doi.org/10.1021/acs.jmedchem.3c00442
Zirkin, B. R., & Papadopoulos, V. (2018). Leydig cells: Formation, function, and regulation. In Biology of Reproduction (Vol. 99, Issue 1, pp. 101–111). Oxford University Press. https://doi.org/10.1093/biolre/ioy059