API

Event: 1609

Key Event Title

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Inhibition, Cytochrome P450 enzyme (CYP17A1) activity

Short name

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Inhibition of Cyp17A1 activity

Biological Context

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Level of Biological Organization
Molecular

Cell term

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Organ term

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Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Cyp17A1 inhibition leads to undescended testes in mammals MolecularInitiatingEvent

Stressors

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Taxonomic Applicability

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Life Stages

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Sex Applicability

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Key Event Description

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Cyp17a1 inhibitors bind in the active site of the enzyme by mimicking endogenous substrate, leading to a reduction in the activity of the enzyme. Cyp17A1 is the single enzyme mediating both 17 alpha-hydroxylase and 17,20-lyase activities, the distinction between the two being functional and not genetic or structural.  Cyp17a1 is found in all the steroidogenic tissues such as the Leydig cells of the testes, the thecal cells of the ovaries and the adrenal cortex. Studies also detected Cyp17a1 activities in  heart, adipose, liver and kidney tissue. CYP17a1 has a decisive function in steroidogenesis by constituting the initial step in a series of biochemical reactions that culminate in synthesis of steroid end-products (testosterone, estradiol, cortisol, and DHEA). Thus, any variation in Cyp17a1’s activity directly or indirectly affect steroidogenesis.12


How It Is Measured or Detected

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Measurement in CYP17 MA-10 wild-type and CYP17 knock down MA-10 clone can be used to assess the effects of a dysfunction in CYP17a1 activity.3


Domain of Applicability

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Evidence for Perturbation by Stressor


Overview for Molecular Initiating Event

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Abiraterone acetate used in androgen deprivation therapy4 , antifungals from the conazoles family5 (Ketonazole, Fadrozole, Imidazole, Prochloraz6…) etc.



References

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1 Storbeck K., Swart P., Africander D., Conradie R., Louw R. and.Swart A.C. (2011) 16α-Hydroxyprogesterone: Origin, biosynthesis and receptor interaction. Molecular and Cellular Endocrinology, 336(1-2): 92-101https://doi.org/10.1016/j.mce.2010.11.016

2 Petrunak E.M., DeVore N.M., Patrick R. Porubsky PR.., and 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 

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 

4 Anitha B. Alex, Sumanta K. Pal, and Neeraj Agarwal (2016) CYP17 inhibitors in prostate cancer: latest evidence and clinical potential. Therapeutic Advances in Medical Oncology, 8(4):267-75  https://doi.org/10.1177/1758834016642370

5 Roelofs M.J., Piersma A.H., van den Berg M. and van Duursen M.B. (2013) The relevance of chemical interactions with CYP17 enzyme activity: assessment using a novel in vitro assay. Toxicology and Applied Pharmacology 1;268(3):309-17 https://doi.org/10.1016/j.taap.2013.01.033 

6 Vinggaard A.M., Christiansen S., Laier P., Poulsen M.E., Breinholt V, Jarfelt K., Jacobsen H., Dalgaard M., Nellemann C. and Hass U. (2005) Perinatal exposure to the fungicide prochloraz feminizes the male rat offspring. Toxicological Sciences, 85:886–897https://doi.org/10.1093/toxsci/kfi150