API

Stressor: 281

Title

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Stressor Overview

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AOPs Including This Stressor

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Events Including This Stressor

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Chemical Table

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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.

Instructions

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 “CAS- preferred name” “JChem InChIKey – preferred name” or “Indigo InChIKey- preferred name” depending on which field you perform the search. 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.

AOP Evidence

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In-utero DNA topoisomerase II poisons leading to infant leukaemia

The properties of the quinone metabolite differed from those of etoposide, and the quinone appeared to function by a different mechanism. Previous studies with quinones and other protein-reactive agents have found that some of these compounds increase levels of topoisomerase II-mediated DNA cleavage by covalently adducting to the enzyme at residues that are distal to the active site. Thus, these agents are termed “covalent topoisomerase II poisons”. It is believed that covalent poisons enhance DNA cleavage, at least in part, by closing the N-terminal gate of the protein.Several lines of evidence suggest that etoposide quinone poisons topoisomerase IIα by this latter, covalent mechanism.

Event Evidence

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In-utero DNA topoisomerase II “poisons-

Etoposide metabolites, ie etoposide quinone, is also a potent topoisomerase IIß poisons. The quinone is able to induce about 4 times more enzyme-mediated DNA clevage than does the parent drug. Furthermore, the potency of etoposide quinone was about 2 times greater against topoisomerase IIß than it is agains topoisomerase IIÞ, and it reacts about 2 to 4 time faster with the ß isoform. The quinone metabolite induces a higher ratio of double - to single strand breaks than the parent chemical, and its activity is less dependent on ATP. Whereas etoposide acts as an interfacial topoisomerase II poison, etoposide quinone displayed all of the hallmarks of a covalent poison: the activity of the metabolite was abolished by reducing agents, and the compound inactivated topoisomerase IIβ when it was incubated with the enzyme prior to the addition of DNA​ (Smith et al. 2014)

Stressor Info

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Chemical/Category Description

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Instructions

To edit the “ Stressor 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 “Stressor 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 “Stressor Description”  section on the page.

Characterization of Exposure

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Instructions

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.

References

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List the bibliographic references to original papers, books or other documents used to support the Stressor.

Instructions

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.