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: 1512


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

Activation of Cyp2E1 leads to Oxidative Stress

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 Leading to Liver Cancer adjacent High Not Specified Francina Webster (send email) Open for citation & comment WPHA/WNT Endorsed

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
Sex Evidence
Mixed High

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 activation has two major outcomes: (1) the production of reactive, electrophilic metabolites, and (2) a significant increase in the half-life of the Cyp2E1 enzyme (Gonzalez 2007, Song, et al. 1989). The former is important because metabolites can go on to produce cellular damage by reacting with cellular nucleophiles. The latter is important because the Cyp2E1 catalytic cycle is prone to uncoupling (i.e., instead of incorporating an oxygen atom in to the substrate, the catalytic cycle is interrupted because a superoxide radical is released), which results in the release of reactive oxygen species (ROS) and an increase in cellular oxidative stress (Lieber 1999).

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
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

It is well known that uncoupling of Cyp2E1 catalytic cycle results in the release of harmful reactive oxygen species in the cell (Lieber 1999). 

Oxidative stress is produced during chronic activation (and uncoupling) of the Cyp2E1 catalytic cycle. The cytochrome P-450 catalytic cycle is known to undergo uncoupling leading to the production of ROS (Gorsky, et al. 1984, Loida and Sligar 1993, Meunier, et al. 2004). If this uncoupling occurs, a molecule of superoxide radical is released, which has the effect of interrupting the P450 catalytic cycle and releasing harmful ROS into the cell. Typically superoxide is converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD), which is further reduced into the hydroxyl radical (OH•), and then to water. Other relevant cellular antioxidants include glutathione, thioredoxin, and peroxiredoxins. However, it is also possible for these ROS to scavenge electrons from cellular macromolecules (proteins, lipids, nucleic acids). Because Cyp2E1 is membrane-bound, ROS most commonly react with lipids and initiate lipid peroxidation.  Further, Cyp2E1 can undergo NADPH-dependent ‘futile cycling’, which produces ROS and contributes to the occurrence of lipid peroxidation (Ekstrom and Ingelman-Sundberg 1989). The cellular sources and effects of ROS, as well as the corresponding enzymes and antioxidants are have been thoroughly reviewed (Nakazawa, et al. 1996). 

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


Caro, A.A., Cederbaum, A.I., 2004. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu. Rev. Pharmacol. Toxicol. 44, 27-42.

Ekstrom, G., Ingelman-Sundberg, M., 1989. Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1). Biochem. Pharmacol. 38, 1313-1319.

Gonzalez, F.J., 2007. The 2006 Bernard B. Brodie Award Lecture. Cyp2e1. Drug metabolism and disposition: the biological fate of chemicals 35, 1-8.

Gorsky, L.D., Koop, D.R., Coon, M.J., 1984. On the stoichiometry of the oxidase and monooxygenase reactions catalyzed by liver microsomal cytochrome P-450. Products of oxygen reduction. J. Biol. Chem. 259, 6812-6817.

Jackson, A.F., Williams, A., Recio, L., Waters, M.D., Lambert, I.B., Yauk, C.L., 2014. Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan. Toxicol. Appl. Pharmacol. 274, 63-77.

Kessova, I.G., Ho, Y.S., Thung, S., Cederbaum, A.I., 2003. Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase. Hepatology 38, 1136-1145.

Lieber, C.S., 1999. Microsomal ethanol-oxidizing system (MEOS): The first 30 years (1968- 1998) - A review. Alcohol. Clin. Exp. Res. 23, 991-1007.

Lu, Y., Cederbaum, A.I., 2008. CYP2E1 and oxidative liver injury by alcohol. Free Radical Biology and Medicine 44, 723-738.

Lu, Y., Wu, D., Wang, X., Ward, S.C., Cederbaum, A.I., 2010. 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.

Meunier, B., de Visser, S.P., Shaik, S., 2004. Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes. Chem. Rev. 104, 3947-3980.

Nakazawa, H., Genka, C., Fujishima, M., 1996. Pathological aspects of active oxygens/free radicals. Jpn. J. Physiol. 46, 15-32.

Nanji, A.A., Zhao, S., Sadrzadeh, S.M., Dannenberg, A.J., Tahan, S.R., Waxman, D.J., 1994. Markedly enhanced cytochrome P450 2E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-ethanol-fed rats. Alcohol. Clin. Exp. Res. 18, 1280-1285.

Song, B.J., Veech, R.L., Park, S.S., Gelboin, H.V., Gonzalez, F.J., 1989. Induction of rat hepatic N-nitrosodimethylamine demethylase by acetone is due to protein stabilization. J. Biol. Chem. 264, 3568-3572.

Tindberg, N., Ingelman-Sundberg, M., 1989. Cytochrome P-450 and oxygen toxicity. Oxygen-dependent induction of ethanol-inducible cytochrome P-450 (IIE1) in rat liver and lung. Biochemistry 28, 4499-4504.

Yang, L., Wu, D., Wang, X., Cederbaum, A.I., 2011. Depletion of cytosolic or mitochondrial thioredoxin increases CYP2E1-induced oxidative stress via an ASK-1-JNK1 pathway in HepG2 cells. Free Radic. Biol. Med. 51, 185-196.