Stressor: 133

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

Phenobarbital

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
Phenobarbital DTXSID5021122 Phenobarbital 50-06-6 DDBREPKUVSBGFI-UHFFFAOYSA-N DDBREPKUVSBGFI-UHFFFAOYSA-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
Activation, Constitutive androstane receptor

There is no evidence text for this event.

Altered gene expression specific to CAR activation, Hepatocytes

Phenobarbital (PB)

1.         The ability of PB to induce members of the CYP2B and CYP3A subfamilies of cytochrome enzymes in the livers of rats and mice as well as a number of other genes involved in xenobiotic metabolism, cell proliferation, energy metabolism and lipid metabolism is well-established and has been demonstrated in multiple studies (Elcombe et al., 2014;  Peffer et al., 2018b;  Whysner et al., 1996;  Yamada et al., 2014). Examination of gene expression profiles of in CAR null mice revealed that not all PB-induced genes are CAR-dependent (Ueda et al., 2002).

2.         PB, TCPOBOP, CITCO were used to develop a CAR-dependent gene expression signature (83 genes) in the mouse liver that can be used to predict CAR activation. TCPOBOP (3 mg/kg body weight) was administered (i.p.) to wild-type and CAR-null mice once, followed by injection with vehicle for 2 consecutive days; CITCO (30 mg/kg body weight) and PB (100 mg/kg body weight) were administered once daily for three consecutive days; livers were isolated from mice 6 h after the last injection (Chua and Moore, 2012;  Oshida et al., 2015a). Genes that are upregulated in the CAR signature include Gadd45b and many associated with xenobiotic metabolism, including Cyp2b10 (Oshida et al., 2015a).

Increase, cell proliferation (hepatocytes)

Phenobarbital

1.         NaPB treatment has been shown to increase replicative DNA synthesis in cultured mouse (Haines et al., 2018c) and rat hepatocytes (Haines et al., 2018c;  Hirose et al., 2009).

2.         NaPB treatment (1 week 500-2500 ppm in the diet) was shown to significantly increase the BrdU labeling index in the livers of male CD-1 mice and male Wistar rats compared to their respective vehicle-treated controls (Yamada et al., 2014).

3.         An increase in replicative DNA synthesis was observed in male and female mice administered 1000 ppm NaPB in the diet for 1 month (Jones et al., 2009).

4.         PB at 0, 10, 50, 100 and 500 mg/kg (ppm) in the diet was administered to 8 week old male rats and male mice for 90 days. A significant induction of hepatic replicative DNA synthesis (as determined by [3H]-thymidine incorporation) was observed in the rat liver at 7 days, but had returned to control levels by 14 days. In mice, there was a significant increase in hepatic replicative DNA synthesis throughout treatment (Kolaja et al., 1996a). In both species, the most pronounced effect was observed in the centrilobular region.

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