This Key Event Relationship 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.

Relationship: 1726


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

CYP2E1 Activation leads to Oxidative Stress in Brain

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 Brendan Ferreri-Hanberry (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 Do not cite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

CYP2E1 is part of the cytochrome P450 family and can participate in the metabolism of endogenous, small and hydrophobic compounds using an oxidation reaction.  When CYP2E1 is activated it can induce ROS formation. Activation of CYP2E1 will also lead to an increased expression of the enzyme itself, which will ultimately increase the formation of ROS. CYP2E1 is expressed at various parts in the human brain, such as cortex, cerebellum, hippocampus, thalamus and stratum. Since the level of defence mechanism in the brain against ROS is lower than in other parts in the body oxidative stress is reached faster.

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

The link between CYP2E1 activation and the formation of ROS, which ultimately leads to oxidative stress, was already made in the 90s. Hydroxyethyl free radicals where found in rat livers after the stimulation of CYP2E1, which eventually leads to liver damage.  As already mentioned in the KE description, oxidative stress is defined as the moment when there is an imbalance between the ROS level and the defence mechanisms which leads to damage in the cell. Research done by Haorah et al. showed that CYP2E1 indeed produces ROS. ROS levels where measured in two different situations, neuron cells where induced with ethanol (inducer of CYP2E1) or neuron cells where induced with ethanol in combination with an inhibitor for CYP2E1. ROS levels in the neuron cells decreased significantly with the inhibitor for CYP2E1 when compared with the situation without the inhibitor for CYP2E1. Three other studies, using different cell types, showed that CYP2E1 KO mice resulted in an increased level of TBARS (marker for lipid peroxidation which is induced by ROS).  Also in two of the three studies a higher level of GSH was detected in CYP2E1 KO mice, indicating a lower level of ROS since GSH is used as a defence mechanism against ROS. Furthermore recent research showed that CYP2E1 induction in granule neurons indeed results in ROS formation, but also that the inducement of CYP2E1 increased the expression of CYP2E1 itself. This was also shown in other studies, with the use of immunofluorescence detection techniques. Since activation of CYP2E1 also leads to a higher expression more ROS will be produced. This is also shown in the difference of CYP2E1 expression in alcoholics and non-drinkers, where the expression of CYP2E1 is far higher in alcoholic liver cells. Finally, oxidative stress is reached earlier in neuron cells because of the higher level of oxygen and the lower permeability of the blood vessels.

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 link between CYP2E1 activation oxidative stress is biological plausible.

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

Many studies are performed with ethanol, which is a well-known inducer of CYP2E1. But ethanol can also induce ROS formation by interfering in other biological pathways or inducing endoplasmic reticulum stress, which eventually can lead to neurotoxicity and neurodegeneration. On the other hand direct evidence is available with the studies described above that CYP2E1 induces ROS. Important studies performed are the WT/KO/KI mice and the detection of further CYP2E1 expression when CYP2E1 is activated.

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

Upadhya, S. C., Tirumalai, P. S., Boyd, M. R., Mori, T. & Ravindranath, V. Cytochrome P4502E (CYP2E) in brain: constitutive expression, induction by ethanol and localization by fluorescence in situ hybridization. Arch. Biochem. Biophys. 373, 23–34 (2000).

Garciá-Suástegui, W. A. et al. The Role of CYP2E1 in the Drug Metabolism or Bioactivation in the Brain. Oxidative Medicine and Cellular Longevity 2017, (2017).

Haorah, J. et al. Mechanism of alcohol-induced oxidative stress and neuronal injury. Free Radic. Biol. Med. 45, 1542–1550 (2008).

Valencia-Olvera, A. C., Morán, J., Camacho-Carranza, R., Prospéro-García, O. & Espinosa-Aguirre, J. J. CYP2E1 induction leads to oxidative stress and cytotoxicity in glutathione-depleted cerebellar granule neurons. Toxicol. Vitr. 28, 1206–1214 (2014).

Luo, J. Autophagy and ethanol neurotoxicity. Autophagy 10, 2099–2108 (2014).

Yang, L. & Cederbaum, A. CYP2E1, oxidative stress and MAPK signaling pathway in alcoholic liver disease. Curr. Top. Toxicol. 7, (2011).

Lakshman, M. R. et al. CYP2E1, Oxidative Stress, Post-translational Modifications and Lipid Metabolism. Subcell. Biochem. 67, 199–233 (2013).

Jimenez-Lopez, J. M. & Cederbaum, A. I. CYP2E1-dependent oxidative stress and toxicity: role in ethanol-induced liver injury. Expert Opin. Drug Metab. Toxicol. 1, 671–685 (2005).

Gonzalez, F. J. Role of cytochromes P450 in chemical toxicity and oxidative stress: Studies with CYP2E1. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis 569, 101–110 (2005).

Albano, E. et al. Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol. Hepatology 23, 155–163 (1996).

Albano, E. Alcohol, oxidative stress and free radical damage. Proc. Nutr. Soc. 65, 278–290 (2006).

Wu, D., Wang, X., Zhou, R., Yang, L. & Cederbaum, A. I. Alcohol steatosis and cytotoxicity: The role of cytochrome P4502E1 and autophagy. Free Radic. Biol. Med. 53, 1346–1357 (2012).

Cederbaum, A. I. Role of CYP2E1 in ethanol-induced oxidant stress, fatty liver and hepatotoxicity. Dig. Dis. 28, 802–811 (2010).

Lu, Y., Wu, D., Wang, X., Ward, S. C. & Cederbaum, A. I. Chronic alcohol-induced liver injury and oxidant stress are decreased in cytochrome P4502E1 knockout mice and restored in humanized cytochrome P4502E1 knock-in mice. Free Radic. Biol. Med. 49, 1406–1416 (2010).

Oneta, C. M. et al. Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase. J. Hepatol. 36, 47–52 (2002).

Lieber, C. S. CYP2E1: From ASH to NASH. Hepatology Research 28, 1–11 (2004).

Emerit, J., Edeas, M. & Bricaire, F. Neurodegenerative diseases and oxidative stress. Biomedicine and Pharmacotherapy 58, 39–46 (2004).

Pereira, R. B., Andrade, P. B. & Valentão, P. A Comprehensive View of the Neurotoxicity Mechanisms of Cocaine and Ethanol. Neurotoxicity Research 28, 253–267 (2015).

Yang, F. & Luo, J. Endoplasmic reticulum stress and ethanol neurotoxicity. Biomolecules 5, 2538–2553 (2015).