Stressor: 281
Title
Stressor Overview
AOPs Including This Stressor
| AOP Name | Evidence |
|---|---|
| Inhibitor binding to topoisomerase II leading to infant leukaemia | High |
Events Including This Stressor
Chemical Table
AOP Evidence
Inhibitor binding to topoisomerase II 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
Binding to (interferes with) topoisomerase II enzyme
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)