Relationship: 1726
Title
Upstream event
CYP2E1 ActivationDownstream event
Oxidative Stress in Brain
Key Event Relationship Overview
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding |
|---|---|---|---|
| CYP2E1 activation and formation of protein adducts leading to neurodegeneration | adjacent | Moderate | Moderate |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
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 Supporting this KER
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
The link between CYP2E1 activation oxidative stress is biological plausible.
Uncertainties and Inconsistencies
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.
Quantitative Understanding of the Linkage
Domain of Applicability
References
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).
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