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Event: 1887

Key Event Title

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

Inhibition of CYP26B1 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

CYP26B1, inhibition

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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

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
Human, rat, mouse	Human, rat, mouse	Moderate	NCBI

Life Stages

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

Life stage	Evidence
All life stages	Moderate

Sex Applicability

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

Term	Evidence
Male	High
Female	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

CYP26B1 and its function

Numerous physiological processes as well as fetal development is dependent on correct levels of retinoic acid (RA). RA homeostasis is tightly regulated and involves, amongst many other factors, breakdown by the Cytochrome P450 enzymes of family 26 (Kedishvili, 2013; White et al, 1997; White et al, 1996). The family consists of the enzymes CYP26A1, CYP26B1, and CYP26C1 (Isoherranen & Zhong, 2019). These RA-metabolizing enzymes convert all-trans-RA to more polar metabolites, including 4-hydroxy-RA and 4-oxo-RA (White et al, 1996; White et al, 2000).

CYP26B1 is particularly important for the clearance of RA in the fetal mouse testis, with knockout models having established its critical role in normal testis development in preventing premature meiotic initiation of male germ cells (Bowles et al, 2018; Bowles et al, 2006; Li et al, 2009; MacLean et al, 2007). CYP26B1 is necessary for steroidogenesis and male reproductive tract formation (Bowles et al, 2018), and may also play a role in maintaining normal spermatogenesis in the adult male mouse (Hogarth et al, 2015). CYP26B1 has been shown to be expressed in the postnatal mouse ovary, where it is proposed to regulate granulosa cell proliferation (Kipp et al, 2011).

In addition to reproductive development, CYP26B1 is important for other aspects of embryonic development. The expression of CYP26B1 is initiated at embryonic day 8 in the mouse hindbrain and is expressed in the limb buds from the beginning of their outgrowth as well as later in many different tissues during organ development including the genital tubercle, craniofacial areas, and spinal cord (Abu-Abed et al, 2002; MacLean et al, 2001; Ross & Zolfaghari, 2011). Consistent with this, Cyp26b1-knockout mice display various developmental defects including severe limb malformations and pups born alive die right after birth due to respiratory distress (Yashiro et al, 2004).

Besides from the important role CYP26B1 plays during fetal development, CYP26B1 is also expressed in multiple tissues in the adult human including adipose tissue, bladder, blood vessels, brain, kidney, adrenals, liver, lung, pancreas, intestines, testis, uterus, and skin (The-Human-Protein-Atlas, 2021; Topletz et al, 2012).

CYP26B1 inhibition as Key Event

The main function of CYP26B1 is to inactivate all-trans RA. The major primary metabolites formed from RA by CYP26B1 are 4-OH-RA and 18-OH-RA (Topletz et al, 2012) and CYP26B1 shows preference for the following substrates: all-trans-RA > 9-cis-RA > 13-cis-RA (Topletz et al, 2012; White et al, 2000). CYP26B1 is regulated by a range of molecular factors but also by RA itself (Isoherranen & Zhong, 2019; White et al, 2000).

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 assays for measuring CYP26B1 inhibition.

CYP26b1 mRNA and protein levels can be measured using various probes, antibodies as well as ELISA kits that are commercially available.

Enzyme activity can be measured in different types of assays including using microsomes measuring conversion of RA to metabolites (Van Wauwe et al, 1988).