AOP ID and Title:

Short Title: From hERG blockade to death

Authors

Egemen Bilgin

 

Status

Abstract

Adverse Outcome Pathways aim to give a precise mechanistic description of relevant toxicological effects. In the current study, an AOP framework is used for increased mortality triggered by drug-mediated blockade of human ether-a-gogo-related gene (hERG) channel. An extensive review of the related scientific literature was conducted for this purpose in order to figure out key events (KEs). The KEs include the inhibition of rapid delayed rectifying potassium current, prolongation of action potential duration, prolongation of QT interval  and Torsades de Pointes. Overall, all these steps clearly indicate that there has been a distruption in cardiac electrophysiology, leading to sudden cardiac death on individual level.

AOP development was performed in parallel with OECD guideline. The postulated AOP is expected to serve as the basis for the development of novel drugs with less risk of sudden cardiac death mainly triggered by hERG channel blockade.

Summary of the AOP

Events

Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)

Key Event Relationships

Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability Taxonomic Applicability Sex Applicability

Homo sapiens

Considerations for Potential Applications of the AOP (optional)

The AOP may be useful in the risk assessment on several types molecules including drugs, as well as other types of chemicals, biocides, or pesticides. This AOP elucidating the pathway from hERG blockade to sudden cardiac death may provide important insights into the potential toxicity of direct and/or indirect hERG inhibitors.

References

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Appendix 1

List of MIEs in this AOP

Event: 2099: hERG channel blockade

Short Name: hERG channel blockade

AOPs Including This Key Event

Biological Context

List of Key Events in the AOP

Event: 2100: Inhibition of rapid delayed rectifying potassium current

Short Name: Inhibition of rapid delayed rectifying potassium current

AOPs Including This Key Event

Biological Context

Event: 1961: Prolongation of Action Potential Duration

Short Name: Prolongation of Action Potential

AOPs Including This Key Event

Biological Context

Event: 1962: Prolongation of QT interval

Short Name: Prolongation of QT interval

AOPs Including This Key Event

Biological Context

Event: 1963: Torsades de Pointes

Short Name: Torsades de Pointes

AOPs Including This Key Event

Biological Context

List of Adverse Outcomes in this AOP

Event: 1964: Sudden cardiac death

Short Name: Sudden cardiac death

AOPs Including This Key Event

Biological Context

Appendix 2

List of Key Event Relationships in the AOP