Stressor: 282

Title

To create a new stressor, from the Listing Stressors page at https://aopwiki.org/stressors click ‘New stressor.’ This will bring you to a page entitled “New Stressor” where a stressor title can be entered. Click ‘Create stressor’ to create a new Stressor page listing the stressor title at the top. More help

Ketoconazole

Stressor Overview

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. More help

AOPs Including This Stressor

This table is automatically generated and lists the AOPs associated with this Stressor. More help

AOP Name	Evidence
Inhibition of CYP7B activity leads to decreased reproductive success via decreased locomotor activity	High
Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior
Inhibition of 11β-hydroxylase leading to decresed population trajectory	High

Events Including This Stressor

This table is automatically generated and lists the Key Events associated with this Stressor. More help

Event Name
CYP7B activity, inhibition
7α-hydroxypregnenolone synthesis in the brain, decreased
decrease, male anogenital distance
Inhibition of CYP26B1 activity
Increased (ectopic) all-trans retinoic acid concentration

Chemical Table

The Chemical Table lists chemicals associated with a stressor. This table contains information about the User’s term for a chemical, the DTXID, Preferred name, CAS number, JChem InChIKey, and Indigo InChIKey.To add a chemical associated with a particular stressor, next to the Chemical Table click ‘Add chemical.’ This will redirect you to a page entitled “New Stressor Chemical.’ The dialog box can be used to search for chemical by name, CAS number, JChem InChIKey, and Indigo InChIKey. Searching by these fields will bring forward a drop down list of existing stressor chemicals formatted as Preferred name, “CAS- preferred name,” “JChem InChIKey – preferred name,” or “Indigo InChIKey- preferred name,” depending on by which field you perform the search. It may take several moments for the drop down list to display. Select an entity from the drop down list and click ‘Add chemical.’ This will return you to the Stressor Page, where the new record should be in the ‘Chemical Table’ on the page.To remove a chemical associated with a particular stressor, in the Chemical Table next to the chemical you wish to delete, click ‘Remove’ and then click 'OK.' The chemical should no longer be visible in the Chemical table. More help

User term	DTXID	Preferred name	Casrn	jchem_inchi_key	indigo_inchi_key
Ketoconazole	DTXSID7029879	Ketoconazole	65277-42-1	XMAYWYJOQHXEEK-OZXSUGGESA-N	XMAYWYJOQHXEEK-OZXSUGGESA-N

AOP Evidence

This table is automatically generated and includes the AOPs with this associated stressor as well as the evidence term and evidence text from this AOP Stressor. More help

Inhibition of CYP7B activity leads to decreased reproductive success via decreased locomotor activity

Conazole is a class of fungicide that inhibits CYP51 14α-lanosterol demethylase activity in yeats and moults, thereby preventing ergosterol synthesis (Hof et al., 2006). In animals, conazoles are known to be less specific than in fungi since they can interfere with various cytochromes P450 activity. For instance, it is clearly demonstrated that ketoconazole directly inhibits CYP7B activity which induces a decrease in 7α-hydroxypregnenolone (Matsunaga et al., 2004, Tsutsui et al., 2008; Toyoda et al., 2012; Ogura et al., 2016).

Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior

There is no evidence text for this AOP

Inhibition of 11β-hydroxylase leading to decresed population trajectory

Steroidogenesis enzyme inhibitors in Cushing’s syndrome European Journal of Endocrinology 172, 6; 10.1530/EJE-14-1014

Event Evidence

This table is automatically generated and includes the Events with this associated stressor as well as the evidence text from this Event Stressor. More help

CYP7B activity, inhibition

It is clearly demonstrated that ketoconazole directly inhibits CYP7B (Matsunaga et al., 2004). It is expected for the other members of the conazole family to have the same effect.

Some other azoles such as clotrimazole can also inhibit CYP7B activity (Liu et al., 2011; Rose et al., 1997).

7α-hydroxypregnenolone synthesis in the brain, decreased

There is no evidence text for this event.

decrease, male anogenital distance

Ketoconazole has been shown to cause decreased male AGD in rats following intrauterine exposure to 50 mg/kg bw/day in one study (Taxvig et al, 2008), but no effect in another study using same dose (Wolf et al, 1999).

Inhibition of CYP26B1 activity

Ketoconazole: Using tazarotenic acid as a substrate in vitro incubations and metabolite production measured by LC-MS/MS showed an IC₅₀ of 190 nM (Foti et al, 2016). Using hamster liver microsomes ketoconazole decreased RA metabolite formation and in vivo, oral ketoconazole administration suppressed metabolite formation after RA dosing in rats (Van Wauwe et al, 1988).

Increased (ectopic) all-trans retinoic acid concentration

Ketoconazole, an azole antifungal that functions by binding and disrupting the action of fungal cytochrome P-450 to disrupt fungal membranes. In mouse testis it has been shown to increase levels of endogenous RA (Bowles et al, 2006).

Stressor Info

Text sections under this subheading include the Chemical/Category Description and Characterization of Exposure. More help

Chemical/Category Description

To edit the Chemical/Category Description” section, on a KER page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.” Scroll down to the “Chemical/Category Description” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page. The new text should appear under the “Chemical/Category Description” section on the page. More help

Characterization of Exposure

To edit the “Characterization of Exposure” section, on a Stressor page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.” Scroll down to the “Characterization of Exposure” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page. The new text should appear under the “Characterization of Exposure” section on the page. More help

References

List of the literature that was cited for this Stressor description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015).To edit the “References” section, on a Stressor page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.” Scroll down to the “References” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page. The new text should appear under the “References” section on the page. More help