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Relationship: 1729


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Protein Adduct Formation leads to Unfolded Protein Response

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
CYP2E1 activation and formation of protein adducts leading to neurodegeneration adjacent Moderate Moderate Jelle Broeders (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 Do not cite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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

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

Life Stage Applicability

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

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Covalent binding of metabolites or other molecules, such as HNE, with key ER proteins can induce ER stress or can cause oxidative damage in the ER. The mechanism is not completely understood. The principle is that modified proteins are not able to be folded in the correct way, leading to accumulation of unfolded proteins in the ER. Another possibility is that key proteins in the ER are altered, which inhibits their function. Ultimately the ER homeostasis will be disturbed, which leads to ER stress and the activation of UPR.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

HNE-modified proteins are detected after lipid peroxidation, as is described in KER 4. More recent research showed that the modified proteins by HNE are also ER proteins, such as protein disulphide isomerase, glucose regulated protein 58/78 and heat shock protein 60. To confirm whether protein-HNE adducts can induce ER stress and UPR, changes in the PERK pathway were monitored. After HNE treatment in rat aortic smooth muscle cells the expression in the PERK pathway increased. Cumaoglu et al. performed a study related to diabetes, and also found that a higher concentration of HNE in cells lead to a higher expression of PERK. Moreover, other proteasomes function in the cell can be carbonylated by CYP2E1 dependent oxidant stress.

For toxicants which can directly form protein adducts which leads to UPR is not much known, certainly not about the mechanism. Cisplatin can bind to microsomal compartments which induce ER stress and ultimately UPR. Metabolites of cyclosporin and acetaminophen can also bind to microsomal compartments with the same effect as cisplatin.

Acetaldehyde and malondialdehyde (product lipid peroxidation) can react together and can form MAA-adducts. There is no direct link with UPR, but the MAA-adducts are very stable. MAA modified proteins are found in the lungs and skin. Further research is needed to detect whether the can interact with ER proteins.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The biological plausibility can be found in literature, but mechanism is not known. For ethanol, the metabolite acetaldehyde specifically, there is no direct link between protein adduct and UPR

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


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

Sapkota, M. & Wyatt, T. A. Alcohol, aldehydes, adducts and airways. Biomolecules 5, 2987–3008 (2015).

Tuma, D. J. Role of malondialdehyde-acetaldehyde adducts in liver injury. Free Radical Biology and Medicine 32, 303–308 (2002).

Foufelle, F. & Fromenty, B. Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacol. Res. Perspect. 4, e00211 (2016).

Haberzettl, P. & Hill, B. G. Oxidized lipids activate autophagy in a JNK-dependent manner by stimulating the endoplasmic reticulum stress response. Redox Biol. 1, 56–64 (2013).

Galligan, J. J. et al. Oxidative stress-mediated aldehyde adduction of GRP78 in a mouse model of alcoholic liver disease: Functional independence of ATPase activity and chaperone function. Free Radic. Biol. Med. 73, 411–420 (2014).

Cumaoglu, A., Arıcıoglu, A. & Karasu, C. Redox status related activation of endoplasmic reticulum stress and apoptosis caused by 4-hydroxynonenal exposure in INS-1 cells. Toxicol. Mech. Methods 24, 362–367 (2014).

Kessova, I. G. & Cederbaum, A. I. The effect of CYP2E1-dependent oxidant stress on activity of proteasomes in HepG2 cells. J Pharmacol Exp Ther 315, 304–312 (2005).

Huličiak, M. et al. Covalent binding of cisplatin impairs the function of Na +/K +-ATPase by binding to its cytoplasmic part. Biochem. Pharmacol. 83, 1507–1513 (2012).

Sadrieh, N. & Thomas, P. E. Characterization of rat cytochrome P450 isozymes involved in the covalent binding of cyclosporin A to microsomal proteins. Toxicol. Appl. Pharmacol. 127, 222–232 (1994).

Shin, N. Y., Liu, Q., Stamer, S. L. & Liebler, D. C. Protein targets of reactive electrophiles in human liver microsomes. Chem. Res. Toxicol. 20, 859–867 (2007).