Alcohol and liver cancer.
Hepatocellular carcinoma is the eighth most frequent cancer in the world, accounting for approximately 500,000 deaths per year. Unlike many malignancies, hepatocellular carcinoma occurs predominantly within the context of known risk factors, with hepatic cirrhosis being the most common precursor to the development of hepatocellular carcinoma. After ethanol ingestion, the liver represents the major site of metabolism. Ethanol metabolism by alcohol dehydrogenase leads to the generation of acetaldehyde and free radicals that bind rapidly to numerous cellular targets, including components of cell signaling pathways and DNA. In addition to direct DNA damage, acetaldehyde depletes glutathione, an antioxidant involved in detoxification. Chronic ethanol abuse leads to induction of hepatocyte microsomal cytochrome P450 2E1, an enzyme that metabolizes ethanol to acetaldehyde and, in doing so, causes further free radical production and aberrant cell function. Cytochrome P450 2E1-dependent ethanol metabolism is also associated with activation of procarcinogens, changes in cell cycle, nutritional deficiencies, and altered immune system responses. The identification of oxidative stress in mediating many deleterious effects of ethanol in the liver has led to renewed interest in the use of dietary antioxidants as therapeutic agents. Included in this group are S-adenosyl-L-methionine and plant-derived flavanoids.
McKillop
Iain H
IH
Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA. imckillo@email.uncc.edu
Schrum
Laura W
LW
D000437:Alcoholism / Q000150:complications; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000453:epidemiology; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000378:metabolism; D018450:Disease Progression; D000431:Ethanol / Q000009:adverse effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D012436:S-Adenosylmethionine / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D012838:Silymarin / Q000627:therapeutic use
D000975:Antioxidants; D002492:Central Nervous System Depressants; D012838:Silymarin; D000431:Ethanol; D012436:S-Adenosylmethionine; D005978:Glutathione