API

Event: 1508

Key Event Title

?

CYP2E1 Activation

Short name

?

CYP2E1 Activation

Biological Context

?

Level of Biological Organization
Molecular

Cell term

?


Organ term

?

Organ term
prefrontal cortex


Key Event Components

?

Process Object Action

Key Event Overview


AOPs Including This Key Event

?

AOP Name Role of event in AOP
CYP2E1 activation and formation of protein adducts leading to neurodegeneration MolecularInitiatingEvent

Stressors

?


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

?



Evidence for Perturbation by Stressor


Overview for Molecular Initiating Event

?



Acetaminophen

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/


Enflurane

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/


Halothane

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/


Isoflurane

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/


Methoxyflurane

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/


Sevoflurane

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/

 


Chemical:584015 (1-~13~C)Aniline

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/

 


Chlorzoxazone

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/


Titanium oxide (TiO)

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/

 


Isoniazid

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/

 


Ethanol

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)

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)

Indiana University. P450 Drug Interaction Table. Available at: http://medicine.iupui.edu/clinpharm/ddis/main-table/


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)