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Event: 1609

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Inhibition, Cytochrome P450 enzyme (CYP17A1) activity

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Inhibition of Cyp17A1 activity

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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Cyp17A1 inhibition leads to undescended testes in mammals	MolecularInitiatingEvent	Bérénice COLLET (send email)	Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

References

List of the literature that was cited for this KE description. More help

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