Oxidative stress, toxicology, and pharmacology of CYP2E1.
This review describes some of the biochemical and toxicological properties of CYP2E1, especially as it relates to alcohol metabolism and toxicity and the establishment of human hepatoma HepG2 cell lines that overexpress human CYP2E1. Ethanol, polyunsaturated fatty acids, and iron were found to be cytotoxic in HepG2 cells that overexpress CYP2E1. GSH appears to be essential in protecting HepG2 cells against the CYP2E1-dependent cytotoxicity, and GSH levels were elevated owing to a twofold increase in activity and expression of glutamate cysteine ligase. We suggest that this up-regulation of GSH synthesis was an adaptive response to attenuate CYP2E1-dependent oxidative stress and toxicity. Induction of a state of oxidative stress appears to play a central role in the CYP2E1-dependent cytotoxicity. Mitochondrial membrane potential decreased in the CYP2E1-expressing HepG2 cells, and this decrease shared similar characteristics with the developing toxicity. Alcohol-dependent liver injury is likely to be a multifactorial process involving several mechanisms. We believe that the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis contribute to the toxic actions of ethanol on the liver.
Caro
Andres A
AA
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA. Andres.Caro@mssm.edu
Cederbaum
Arthur I
AI
D000818:Animals; D006528:Carcinoma, Hepatocellular; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D000431:Ethanol / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism / Q000473:pathology; D008862:Microsomes, Liver / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017382:Reactive Oxygen Species; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione