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Event: 2321

Key Event Title

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

Decreased, CYP11A1 activity

Short name

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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

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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

Term	Scientific Term	Evidence	Link
mammals	mammals	High	NCBI

Life Stages

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

Life stage	Evidence
All life stages	High

Sex Applicability

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

Term	Evidence
Mixed	High

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

Conversion of cholesterol into pregnenolone is the first step of steroidogenesis. All steroid hormones descend from pregnenolone. The enzyme responsible for this conversion is CYP11A1. CYP11A1, also known as cytochrome P450 side-chain cleavage enzyme (P450scc), is located in the inner mitochondrial membrane. The conversion of cholesterol to pregnenolone by CYP11A1 is the initial rate limiting enzymatic step (Payne & Hales, 2004; Yamazaki, 2014). Another protein possesses an important role in the conversion conducted by CYP11A1; Steroidogenic acute regulatory protein (StAR). StAR is essential for this step to take place as it promotes cholesterol transport to the inner

mitochondrial membrane. This makes cholesterol available to CYP11A1 to begin steroidogenesis. This transport is a rate-limiting step for steroidogenesis (Chien et al., 2017).

CYP11A1 is expressed in the brain and steroidogenic cells, and therefore present in the adrenals and gonads as well as the placenta. Specifically, it is expressed in Leydig cells of the testis, the theca, granulosa cells, and corpus luteum of the ovary as well as the syncytial trophoblasts of the placenta (Chien et al., 2017; Payne & Hales, 2004).

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

There are no OECD validated standardized tests available for CYP11A1 enzyme activity assay.

However, enzyme activity has been measured in many studies by using transfected cells (such as NCI-H295R cells or COS cells) with CYP11A1. Addition of the substrate 22(R)-hydroxycholesterol, which does not require StAR activity, allows conversion to pregnenolone by CYP11A1. Pregnenolone levels can then be measured with LC/MS-MS showcasing the activity of CYP11A1 (Goursaud et al., 2018; Karimaa et al., 2022; Parajes et al., 2011).

Domain of Applicability

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

Taxonomic applicability

The CYP enzymes that are part of the P450 enzyme family are expressed vertebrates. However, this KE focuses on its role in mammals. It is well conserved and essential for all mammals (Payne & Hales, 2004; Slominski et al., 2015).

Life stage applicability

CYP11A1 is expressed during embryogenesis, throughout development and increases during puberty and adulthood. This KE is therefore applicable throughout all life stages (Payne & Hales, 2004).

Sex applicability

CYP11A1 is essential for survival and development of both males and females as it is needed for the start of steroidogenesis creating all steroid hormones (Payne & Hales, 2004).

References

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

Chien, Y., Rosal, K., & Chung, B. (2017). Function of CYP11A1 in the mitochondria. Molecular and Cellular Endocrinology, 441, 55–61. https://doi.org/10.1016/j.mce.2016.10.030

Goursaud, C., Mallet, D., Janin, A., Menassa, R., Tardy-Guidollet, V., Russo, G., Lienhardt-Roussie, A., Lecointre, C., Plotton, I., Morel, Y., & Roucher-Boulez, F. (2018). Aberrant Splicing Is the Pathogenicity Mechanism of the p.Glu314Lys Variant in CYP11A1 Gene. Frontiers in Endocrinology, 9. https://doi.org/10.3389/fendo.2018.00491

Karimaa, M., Riikonen, R., Kettunen, H., Taavitsainen, P., Ramela, M., Chrusciel, M., Karlsson, S., Rummakko, P., Simola, O., Wohlfahrt, G., Hakulinen, P., Vuorela, A., Joensuu, H., Utriainen, T., Fizazi, K., & Oksala, R. (2022). First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis. Molecular Cancer Therapeutics, 21(12), 1765–1776. https://doi.org/10.1158/1535-7163.MCT-22-0115

Parajes, S., Kamrath, C., Rose, I. T., Taylor, A. E., Mooij, C. F., Dhir, V., Grötzinger, J., Arlt, W., & Krone, N. (2011). A Novel Entity of Clinically Isolated Adrenal Insufficiency Caused by a Partially Inactivating Mutation of the Gene Encoding for P450 Side Chain Cleavage Enzyme (CYP11A1).

The Journal of Clinical Endocrinology & Metabolism, 96(11), E1798–E1806. https://doi.org/10.1210/jc.2011-1277

Payne, A. H., & Hales, D. B. (2004). Overview of Steroidogenic Enzymes in the Pathway from Cholesterol to Active Steroid Hormones. Endocrine Reviews, 25(6), 947–970. https://doi.org/10.1210/er.2003-0030

Slominski, A. T., Li, W., Kim, T.-K., Semak, I., Wang, J., Zjawiony, J. K., & Tuckey, R. C. (2015). Novel activities of CYP11A1 and their potential physiological significance. The Journal of Steroid Biochemistry and Molecular Biology, 151, 25–37. https://doi.org/10.1016/j.jsbmb.2014.11.010

Yamazaki, H. (Ed.). (2014). Fifty Years of Cytochrome P450 Research. Springer Japan. https://doi.org/10.1007/978-4-431-54992-5