Role of microsomal enzymes in development of alcoholic liver diseases.
Chronic ethanol consumption results in the proliferation of the membranes of the smooth endoplasmic reticulum. Although these microsomal changes can be interpreted as adaptive alterations secondary to induction of the membranes after chronic ethanol ingestion, some injurious consequences may ensue. Accelerated ethanol metabolism results in enhanced production of acetaldehyde and exacerbation of its various toxic manifestations including enhanced lipid peroxidation. The latter may also be promoted more directly through enhanced free radical formation by the induced microsomes and cytochrome P4502E1 (CYP2E1). Ethanol-inducible CYP2E1 is of interest because of its ability to metabolize and activate many toxicologically important substrates including ethanol, CCl(4), acetaminophen, and N-nitrosodimethylamine, to more toxic products. Major interest in CYP2E1 reflects the ability of this enzyme to oxidize ethanol, to generate reactive products from ethanol oxidation (e.g. acetaldehyde and 1-hydroxyethyl radical), to activate various agents including CCl(4) and acetaminophen into reactive products, and to generate reactive oxygen species. There is considerable interest in the role of ethanol-induced oxidative stress and generation of reactive oxygen species in the mechanisms by which ethanol becomes hepatotoxic. To understand the basic effects and actions of CYP2E1, an approach has been established to utilize the cell lines that constitutively express human CYP2E1. This review article briefly describes a role of microsomal enzymes in the development of alcoholic liver injury as well as the usefulness of this cell line to further clarify the mechanisms of CYP2E1-related hepatotoxicity.
Konishi
Masahiro
M
Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Ishii
Hiromasa
H
D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology; D000431:Ethanol / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology; D015227:Lipid Peroxidation; D008108:Liver Diseases, Alcoholic / Q000201:enzymology* / Q000503:physiopathology*; D008862:Microsomes, Liver / Q000201:enzymology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species
D017382:Reactive Oxygen Species; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1