The Role of CYP2E1 in the Drug Metabolism or Bioactivation in the Brain

Abstract

Organisms have metabolic pathways that are responsible for removing toxic agents. We always associate the liver as the major organ responsible for detoxification of the body; however this process occurs in many tissues. In the same way, as in the liver, the brain expresses metabolic pathways associated with the elimination of xenobiotics. Besides the detoxifying role of CYP2E1 for compounds such as electrophilic agents, reactive oxygen species, free radical products, and the bioactivation of xenobiotics, CYP2E1 is also related in several diseases and pathophysiological conditions. In this review, we describe the presence of phase I monooxygenase CYP2E1 in regions of the brain. We also explore the conditions where protein, mRNA, and the activity of CYP2E1 are induced. Finally, we describe the relation of CYP2E1 in brain disorders, including the behavioral relations for alcohol consumption via CYP2E1 metabolism.

Figure 1

Exogenous agents and pathologies associated with CYP2E1 activity and expression in brain. LPS: lipopolysaccharide; MPP+: 1-methyl-4-phenylpyridinium; MPTP: 1-metil-4-fenil-1,2,3,6-tetrahydropyridine.

Figure 2

Ethanol oxidation by CYP2E1 results in an increase of ROS and oxidative stress. Ethanol can induce the expression/activity of CYP2E1 resulting in an increase of ROS and cellular damage. Increased ROS levels damage biomolecules such as lipid, protein, DNA, and mitochondria, starting a feedback cycle of ROS production-damage. ALD: aldehyde dehydrogenase; CYP2E1: cytochrome isoform 2E1; ^•OH: hydroxyl radical; ^•O₂⁻: superoxide anion radical; H₂O₂: hydrogen peroxide; Fe²⁺: ferrous iron; NADPH: nicotinamide adenine dinucleotide phosphate (oxidized form); NADP⁺: nicotinamide adenine dinucleotide phosphate (reduced form).