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Event: 1508
Key Event Title
CYP2E1 Activation
Short name
Biological Context
Level of Biological Organization |
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Molecular |
Cell term
Organ term
Organ term |
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prefrontal cortex |
Key Event Components
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
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CYP2E1 activation and formation of protein adducts leading to neurodegeneration | MolecularInitiatingEvent | Jelle Broeders (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Life Stages
Sex Applicability
Key Event Description
CYP2E1 is an enzyme which is part of the cytochrome P450 family. It participates in the metabolism of endogenous, small and hydrophobic compounds using an oxidation reaction. CYP2E1 requires phospholipids, NADPH, and NADPH-cytochrome P450 reductase as a cofactor for catalytic activity in vitro. The level of CYP2E1 in the brain of a rat is significantly low, only 25% of what is found in rat liver cells. Inside a brain cell of a rat the highest level of CYP2E1 is found in the mitochondria and the endoplasmic reticulum. In human brain samples expression of CYP2E1 was found in the amygdala and prefrontal cortex. CYP2E1 is also known to activate toxic related compounds (see stressors). Another important consideration is that CYP2E1 is part of the microsomal ethanol oxidizing system. When CYP2E1 is stimulated at constant rate the concentration of the enzyme in the cell will rise. (Garciá-Suástegui, W. A. et al., 2017; Howard, L. A. et al., 2003; Neafsey, P. et al., 2009; Toselli, F. et al, 2015; Zimatkin, S. M. et al, 2006)
How It Is Measured or Detected
Visualization of CYP2E1 can be done with immunofluorescence in cultured neuron cells. With the use of this technique, an increase or decrease of CYP2E1 can be measured. A rabbit polyclonal antibody for CYP2E1 is used in combination with a FITC-conjugated anti-rabbit antibody. With the FITC tag the CYP2E1 proteins can be made visible using fluorescence. Measurements are done with a confocal laser-scanning microscope. Another way of visualization can be done with the western blot analysis. (Garciá-Suástegui, W. A. et al., 2017; Valencia-Olvera, A. C. et al., 2014)
Domain of Applicability
References
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)
Howard, L. A., Miksys, S., Hoffmann, E., Mash, D. & Tyndale, R. F. Brain CYP2E1 is induced by nicotine and ethanol in rat and is higher in smokers and alcoholics. Br. J. Pharmacol. 138, 1376–1386 (2003).
Neafsey, P. et al. Genetic polymorphism in CYP2E1: Population distribution of CYP2E1 activity. Journal of Toxicology and Environmental Health - Part B: Critical Reviews 12, 362–388 (2009)
Toselli, F. et al. Expression of CYP2E1 and CYP2U1 proteins in amygdala and prefrontal cortex: Influence of alcoholism and smoking. Alcohol. Clin. Exp. Res. 39, 790–797 (2015)
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)
Zimatkin, S. M., Pronko, S. P., Vasiliou, V., Gonzalez, F. J. & Deitrich, R. A. Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol. Clin. Exp. Res. 30, 1500–1505 (2006)