Alcohol and Retinoids

Kato

Alcoholism Clin & Exp Res

et al. 2006

Section: Discussionmentioning

confidence: 99%

Esophageal Squamous Cell Carcinoma and Aldehyde Dehydrogenase‐2 Genotypes in Japanese Females

Kato

Alcoholism Clin & Exp Res

et al. 2006

“…Interference with vitamin A metabolism and its nutritional status is one of the major alterations caused by alcohol (Crabb et al 2001;Wang, 2001). Lower hepatic vitamin A levels in alcoholics have been well documented (Leo & Lieber, 1982).…”

Section: Retinoidsmentioning

confidence: 99%

Alcohol and cancer: genetic and nutritional aspects

Pöschl¹,

Stickel

Wang

et al. 2004

Proc. Nutr. Soc.

Chronic alcohol consumption is a major risk factor for cancer of upper aero-digestive tract (oro-pharynx, hypopharynx, larynx and oesophagus), the liver, the colo-rectum and the breast. Evidence has accumulated that acetaldehyde is predominantly responsible for alcoholassociated carcinogenesis. Acetaldehyde is carcinogenic and mutagenic, binds to DNA and protein, destroys the folate molecule and results in secondary cellular hyper-regeneration. Acetaldehyde is produced by mucosal and cellular alcohol dehydrogenase, cytochrome P450 2E1 and through bacterial oxidation. Its generation and/or its metabolism is modulated as a result of polymorphisms or mutations of the genes responsible for these enzymes. Acetaldehyde can also be produced by oral bacteria. Smoking, which changes the oral bacterial flora, also increases salivary acetaldehyde. Cigarette smoke and some alcoholic beverages, such as Calvados, contain acetaldehyde. In addition, chronic alcohol consumption induces cytochrome P450 2E1 enxyme activity in mucosal cells, resulting in an increased generation of reactive oxygen species and in an increased activation of various dietary and environmental carcinogens. Deficiencies of riboflavin, Zn, folate and possibly retinoic acid may further enhance alcohol-associated carcinogenesis. Finally, methyl deficiency as a result of multiple alcoholinduced changes leads to DNA hypomethylation. A depletion of lipotropes, including methionine, choline, betaine and S-adenosylmethionine, as well as folate, results in the hypomethylation of oncogenes and may lead to DNA strand breaks, all of which are associated with increased carcinogenesis.Chronic alcohol consumption: Cancer: Acetaldehyde: Cytochrome P450 2E1:Alcohol-nutrient interactionsChronic excessive alcohol consumption is a strong risk factor for cancer of the upper aero-digestive tract (oral cavity, pharynx, hypopharynx, larynx, oesophagus), the liver, the colo-rectum and the breast. A great number of epidemiological studies have demonstrated the correlation between alcohol ingestion and the occurrence of cancer in these organs . These studies clearly show that the ingestion of all types of alcoholic beverage is associated with an increased cancer risk, which suggests that ethanol is the common ingredient that causes this effect. The exact mechanism of ethanol-associated carcinogenesis has remained obscure, since ethanol is not a carcinogen. Multiple mechanisms are involved in alcoholassociated cancer development, including the effect of acetaldehyde (AL; the first metabolite of ethanol oxidation), the induction of cytochrome P450 2E1 (CYP2E1) leading to the generation of reactive oxygen species and enhanced procarcinogen activation, modulation of cellular regeneration and nutritional deficiencies. These mechanisms have been the subject of recent reviews ). In the present paper major emphasis is given to the most recent observations contributing to the elucidation of the mechanisms involved in alcohol-associated carcinogenesis, such as genetic factors and alcohol-nut...

“…hronic alcohol consumption interferes with the intake and metabolism of numerous microand macronutrients and may, therefore, result in malnutrition (1,2). Interference with vitamin A turnover is particularly important, since excess alcohol intake leads to a striking depletion of hepatic vitamin A stores both in experimental animals (3) and in alcoholics (4). In humans, vitamin A deficiency can cause night blindness (5), sexual dysfunction (6), and has been associated with birth defects (7) as well as with alcohol-mediated carcinogenesis (8).…”

mentioning

confidence: 99%

“…Unfortunately, high doses of vitamin A (>100,000 IU/day) are hepatotoxic and can even lead to the development of liver cirrhosis when taken over a period of weeks or months (9,10). Chronic alcohol consumption has been shown to further enhance this intrinsic hepatotoxicity, and it has been demonstrated that liver damage can occur with vitamin A doses as low as 7,500-10,000 IU/day, which is well in the range of doses commonly found in commercial supplements (3,6). An explanation for the enhanced vitamin A hepatotoxicity could be that alcohol-induced microsomal enzymes may generate high amounts of toxic metabolites from various retinoids that add to alcohol-induced liver injury (4).…”

mentioning

confidence: 99%

Hepatotoxicity of alcohol‐induced polar retinol metabolites involves apoptosis via loss of mitochondrial membrane potential

et al. 2005

Chronic alcohol consumption depletes hepatic vitamin A stores. However, vitamin A supplementation is hepatotoxic, which is further potentiated by concomitant alcohol consumption. It was suggested that polar retinol metabolites generated by alcohol-inducible cytochrome P4502E1 aggravate liver damage. However, experimental evidence supporting this hypothesis is lacking. To elucidate the effects of polar retinol metabolites on cultured HepG2 cells and primary rat hepatocytes, polar retinol metabolites were extracted from liver tissues of rats fed either an alcoholic or isocaloric control Lieber-DeCarli diet. Cell toxicity assays included morphology assessment, trypan blue exclusion test, and LDH/AST leakage. Staining for DAPI and acridine orange, FACS analysis, and Western blot for cleaved caspase-9 and -3 were used to detect apoptosis. Polar retinol metabolites caused marked cytotoxicity in a concentration- and time-dependent manner in both cell types reflected by morphological changes, a dramatic increase in trypan blue positive cells, and LDH/AST leakage. Toxicity was due to apoptosis, as demonstrated by a time-dependent increase of sub-G1 cellular events, a rapid loss of mitochondrial membrane potential, and a time-dependent activation of caspase-9 and -3. No toxicity was found with equivalent doses of the control extract from nonalcoholic rats. We demonstrate that polar retinol metabolites cause marked hepatocyte death through the induction of apoptosis.