This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Event: 2118

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Succinate dehydrogenase, inhibited

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

SDH, inhibited

Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
hepatocyte

Organ term

Organ term
liver parenchyma

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
succinate dehydrogenase activity		decreased
FAD metabolic process	succinate dehydrogenase complex	decreased
succinate metabolic process	succinate dehydrogenase complex	decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Succinate dehydrogenase inhibition leading to increased insulin resistance	MolecularInitiatingEvent	Evgeniia Kazymova (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Adult	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Male	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Succinate dehydrogenase (SDH, EC1.3.5.1 (Brenda, IntEnz)) links the tricarboxylic acid (TCA) cycle to Complex II of the electron transport chain of the mitochondria in eukaryotic cells, feeding in reducing equivalents via FAD, concomitant with the reduction of succinate to fumarate. It is sensitive to reversible inhibition by molecules that can bind to it, and reduce the flux from succinate and FAD to fumarate and FADH₂. Consequences of inhibition can include reduction in flux through the TCA cycle, and reducion in mitochondrial electron transport.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Succinate dehydrogenase activity is generally measured by the spectrophotometric detection of colour change in the presence of an electron acceptor and succinate (succinic acid) as substrate, e.g. Franco-Iborra and Tanji, 2020.

Partial reactions of the mitochondrial electron transport chain (ETC) from succinate to an excess of cytochrome c as electron receptor can be used to estimate succinate dehydrogenase activity. Inhibition of cytochrome c reduction by putative inhibitors can be confirmed as acting through SDH inhibition if the rate of reduction is restored by addition of NADH, which can feed electrons into the ETC at cytochrome b-c₁, thus bypassing succinct inhibition. Lysed mitochondria are used to prevent the possibility of rate reduction by mitochondrial succinate import (Melnick and Schiller, 1985).

Alteration in rate of colour change in the presence of a putative inhibitor determining the strength of that inhibition.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

SDH inhibition by phthalate esters has been measured and quantified in mitochondria of hepatocytes of adult male CD rats (Melnick and Schiller, 1982; Melnick and Schiller, 1985). Inter-species differences in SDH structure may lead to different susceptibilities in different taxa.

References

List of the literature that was cited for this KE description. More help

Brenda, "Information on EC 1.3.5.1 - succinate dehydrogenase", https://www.brenda-enzymes.org/enzyme.php?ecno=1.3.5.1, accessed 28/04/2023.

Franco-Iborra, S. and Tianjin, K. (2020), "Succinate dehydrogenase" in Methods in Cell Biology

IntEnz, "IntEnz Enzyme Nomenclature, EC 1.3.5.1", https://www.ebi.ac.uk/intenz/query?cmd=SearchID&id=1525&view=INTENZ, accessed 28/04/2023.

Melnick, R.L. and Schiller, C.M. (1982), "Mitochondrial toxicity of phthalate esters", Environmental Healh Perspectives, Vol 45, pp51-56.

Melnick, R.L. and Schiller, C.M. (1985), "Effect of phthalate esters on energy coupling and succinate oxidation in rat liver mitochondria", Toxicology, Vol 34, pp13-27.