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Relationship: 3519

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Decreased, CYP11A1 activity leads to Decreased, Pregnenolone levels

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Decreased, CYP11A1 activity

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Decreased, Pregnenolone levels

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
mammals	mammals	High	NCBI

Sex Applicability

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

Sex	Evidence
Mixed	High

Life Stage Applicability

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

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Cytochrome CYP11A1 is a vital enzyme that catalyses the first rate-limiting enzymatic step of steroidogenesis. It is needed for the conversion of cholesterol into pregnenolone, the precursor of all steroid hormones (Payne & Hales, 2004; Yamazaki, 2014). This occurs in the mitochondria with the help of the protein StAR (steroidogenic acute regulatory protein), needed for the transport of cholesterol from the outer to the inner mitochondrial membrane where CYP11A1 is located. This permits the conversion of cholesterol into pregnenolone (Chien et al., 2017; Yamazaki, 2014). Therefore, if CYP11A1 activity decreases, less pregnenolone will be produced, decreasing its levels.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

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

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The relationship between CYP11A1 activity and pregnenolone levels is well established as canonical knowledge. Studies using knockout models or observing CYP11A1 deficiencies/mutations have clearly highlighted the importance of this enzyme to produce pregnenolone and therefore all downstream steroid hormones, including sex hormones and adrenal hormones. Null CYP11A1 mice can live between 0-7 days with no steroid hormone levels detected. They can be rescued with daily injections of corticoids, but they have insufficient development of the hypothalamus-pituitary- adrenal axis and reproductive development. Additionally, humans with CYP11A1 deficiency lack steroid production (Hu et al., 2002; Kim et al., 2008; Miller & Auchus, 2011; Tajima et al., 2001; Yamazaki, 2014).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Specific small molecule inhibitors have been developed, such as ODM-208, and were shown to reduce CYP11A1 activity through the inhibition of pregnenolone synthesis (ex: IC50 of 15nmol/L) and therefore, the other downstream steroid hormones in NCI-H295R cells (Karimaa et al., 2022).

Azoles, such as ketoconazole and posaconazole, were also shown to inhibit CYP11A1 activity in a reconstituted system in vitro which is reflected by the decrease of pregnenolone synthesis (more than 65%) (Mast et al., 2013).

These are just two examples of compounds inhibiting CYP11A1 highlighting how inhibition of CYP11A1 activity leads to decreased levels of pregnenolone.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic applicability

CYP11A1 as well as pregnenolone are expressed in all steroidogenic tissues in all vertebrates, although this KER is focused on mammals (Payne & Hales, 2004; Yamazaki, 2014).

Life stage applicability

The conversion of cholesterol to pregnenolone is needed throughout all life stages for correct development and survival (Payne & Hales, 2004; Yamazaki, 2014).

Sex applicability

It is essential for steroidogenesis equally in males and females (Payne & Hales, 2004; Yamazaki, 2014).

References

List of the literature that was cited for this KER 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

Hu, M.-C., Hsu, N.-C., El Hadj, N. Ben, Pai, C.-I., Chu, H.-P., Wang, C.-K. L., & Chung, B. (2002). Steroid Deficiency Syndromes in Mice with Targeted Disruption of Cyp11a1. Molecular Endocrinology, 16(8), 1943–1950. https://doi.org/10.1210/me.2002-0055

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

Kim, C. J., Lin, L., Huang, N., Quigley, C. A., AvRuskin, T. W., Achermann, J. C., & Miller, W. L. (2008). Severe Combined Adrenal and Gonadal Deficiency Caused by Novel Mutations in the Cholesterol Side Chain Cleavage Enzyme, P450scc. The Journal of Clinical Endocrinology & Metabolism, 93(3), 696–702. https://doi.org/10.1210/jc.2007-2330

Mast, N., Linger, M., & Pikuleva, I. A. (2013). Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents. Molecular and Cellular Endocrinology, 371(1–2), 100–106. https://doi.org/10.1016/j.mce.2012.10.013

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

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

Tajima, T., Fujieda, K., Kouda, N., Nakae, J., & Miller, W. L. (2001). Heterozygous Mutation in the Cholesterol Side Chain Cleavage Enzyme (P450scc) Gene in a Patient with 46,XY Sex Reversal and Adrenal Insufficiency. The Journal of Clinical Endocrinology & Metabolism, 86(8), 3820–3825. https://doi.org/10.1210/jcem.86.8.7748

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