Stressor: 406

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

CITCO

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

Events Including This Stressor

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

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
CITCO DTXSID4040761 CITCO 338404-52-7 ZQWBOKJVVYNKTL-AUEPDCJTSA-N ZQWBOKJVVYNKTL-AUEPDCJTSA-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

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
Altered gene expression specific to CAR activation, Hepatocytes

CITCO [6-(4-chlorophenyl)-imidazo(2,1-b)thiazole-5-carbaldehyde]

1.         CITCO was identified as a CAR activator using an in vitro fluorescence-based CAR activation assay, and incubation of primary human hepatocytes isolated from two donors with 1 µM CITCO for 48 h resulted in the transcriptional upregulation of selected genes involved in xenobiotic metabolism, including the prototypical CAR target gene CYP2B6 (Maglich et al., 2003).

2.         Genome-wide transcriptional profiling performed on primary human hepatocytes isolated from six individual donors exposed to 1 µM CITCO for 24 h resulted in the modulation of genes primarily involved in xenobiotic metabolism including CYP2B6, CYP2B7P1 and CYP2A7 (Kandel et al., 2016).

3.         WT and hCAR-KO HepaRG cells (human hepatic cell line) were exposed to vehicle or 1 µM CITCO for 24 h, and mRNA was subjected to global gene expression analysis. Comparative analyses identified both previously identified CAR-responsive genes and novel genes that were associated with hCAR activation (Li et al., 2015). These experiments also demonstrated that CITCO achieved CYP2B6 induction predominantly via hCAR activation, whereas phenobarbital induced CYP2B6 by both hCAR and hPXR activation. Many of the genes that were differentially expressed via hCAR activation reflected an inhibition of cell cycle progression (i.e. cell proliferation) in these human HepaRG cultures. These cell cycle/proliferation related pathways repressed by hCAR activation included the TGF-β, p53 and Jak-STAT pathways. In addition, the known role of activators of mCAR in mouse liver for controlling lipogenesis via gene expression changes was not apparent in human HepRG cells after treatments with known hCAR activators.

4.         In contrast to the results in HepaRG cells (above), immortalized human hepatocytes (IHH) incubated with 1 µM CITCO for 48 h resulted in the induction of prototypical CAR-responsive gene CYP2B6, and genes/transcription factors involved in lipid metabolism that could suggest a lipogenic response in human liver (Marmugi et al., 2016).

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