The role of CYP2E1 in alcohol metabolism and sensitivity in the central nervous system

Abstract

Ethanol consumption has effects on the central nervous system (CNS), manifesting as motor incoordination, sleep induction (hypnosis), anxiety, amnesia, and the reinforcement or aversion of alcohol consumption. Acetaldehyde (the direct metabolite of ethanol oxidation) contributes to many aspects of the behavioral effects of ethanol. Given acetaldehyde cannot pass through the blood brain barrier, its concentration in the CNS is primarily determined by local production from ethanol. Catalase and cytochrome P450 2E1 (CYP2E1) represent the major enzymes in the CNS that catalyze ethanol oxidation. CYP2E1 is expressed abundantly within the microsomes of certain brain cells and is localized to particular brain regions. This chapter focuses on the discussion of CYP2E1 in ethanol metabolism in the CNS, covering topics including how it is regulated, where it is expressed and how it influences sensitivity to ethanol in the brain.

Figure 1. Metabolic pathways of ethanol metabolism in the Central Nervous System (CNS)

Three enzymes are responsible for oxidizing ethanol to acetaldehyde: alcohol dehydrogenase (ADH), catalase and cytochrome P450 2E1 (CYP2E1). Acetaldehyde is further oxidized to acetate by acetaldehyde dehydrogenase (ALDH). Acetaldehyde is responsible for many of the behavioral effects associated with ethanol consumption. The contribution of each enzyme to total ethanol oxidation occurring in the CNS is as follows: catalase, serving as the primary enzyme, accounts for 60%; CYP2E1 is inducible and accounts for 20%; the remaining 20% is unknown but is thought to involve ADH. Isoforms of ADH present in the CNS have a wide range of affinity for ethanol.