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Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis.

Payne CM, Bernstein C, Dvorak K, Bernstein H - Clin Exp Gastroenterol (2008)

Bottom Line: Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis.The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy.Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona, USA.

ABSTRACT
Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.

No MeSH data available.


Related in: MedlinePlus

The primary bile acids, cholic acid and chenodeoxycholic acid, are formed in the liver from cholesterol and conjugated, usually with glycine or taurine. They are then secreted into the gall bladder. From the gall bladder, glyco-and tauro- conjugated primary bile acids are released into the duodenum to aid in the digestion of fats. In the terminal ileum and in the cecum, the primary bile acids are deconjugated. Further, in the cecum, they are dehydroxylated through the action of bacterial 7-alpha dehydroxylases. By this reaction, cholic acid and chenodeoxycholic acid are converted to the more genotoxic-hydrophobic bile acids deoxycholic acid and lithocholic acid, respectively.
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f1-ceg-1-019: The primary bile acids, cholic acid and chenodeoxycholic acid, are formed in the liver from cholesterol and conjugated, usually with glycine or taurine. They are then secreted into the gall bladder. From the gall bladder, glyco-and tauro- conjugated primary bile acids are released into the duodenum to aid in the digestion of fats. In the terminal ileum and in the cecum, the primary bile acids are deconjugated. Further, in the cecum, they are dehydroxylated through the action of bacterial 7-alpha dehydroxylases. By this reaction, cholic acid and chenodeoxycholic acid are converted to the more genotoxic-hydrophobic bile acids deoxycholic acid and lithocholic acid, respectively.

Mentions: Sporadic colon cancer is caused predominantly by dietary factors, most notably a high-fat diet accompanied by low intake of micronutrients (folate, niacin, zinc), antioxidants and other plant phytochemicals. A high intake of fat induces the release of bile acids from the gall bladder into the small intestine. Bacteria in the colonic lumen then convert conjugated and hydrophilic bile acids to unconjugated, hydrophobic bile acids such as deoxycholic acid and lithocholic acid (Figure 1). These hydrophobic bile acids, deoxycholic acid in particular, have been reported to be multiple stress inducers and at high physiologic levels can create chaos within colon epithelial cells. These stresses include membrane perturbation, oxidative DNA damage, decrease in DNA repair proteins, mitotic stress, micronuclei formation, mitochondrial damage (metabolic stress) and endoplasmic reticulum (ER) stress (Figure 2).


Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis.

Payne CM, Bernstein C, Dvorak K, Bernstein H - Clin Exp Gastroenterol (2008)

The primary bile acids, cholic acid and chenodeoxycholic acid, are formed in the liver from cholesterol and conjugated, usually with glycine or taurine. They are then secreted into the gall bladder. From the gall bladder, glyco-and tauro- conjugated primary bile acids are released into the duodenum to aid in the digestion of fats. In the terminal ileum and in the cecum, the primary bile acids are deconjugated. Further, in the cecum, they are dehydroxylated through the action of bacterial 7-alpha dehydroxylases. By this reaction, cholic acid and chenodeoxycholic acid are converted to the more genotoxic-hydrophobic bile acids deoxycholic acid and lithocholic acid, respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108627&req=5

f1-ceg-1-019: The primary bile acids, cholic acid and chenodeoxycholic acid, are formed in the liver from cholesterol and conjugated, usually with glycine or taurine. They are then secreted into the gall bladder. From the gall bladder, glyco-and tauro- conjugated primary bile acids are released into the duodenum to aid in the digestion of fats. In the terminal ileum and in the cecum, the primary bile acids are deconjugated. Further, in the cecum, they are dehydroxylated through the action of bacterial 7-alpha dehydroxylases. By this reaction, cholic acid and chenodeoxycholic acid are converted to the more genotoxic-hydrophobic bile acids deoxycholic acid and lithocholic acid, respectively.
Mentions: Sporadic colon cancer is caused predominantly by dietary factors, most notably a high-fat diet accompanied by low intake of micronutrients (folate, niacin, zinc), antioxidants and other plant phytochemicals. A high intake of fat induces the release of bile acids from the gall bladder into the small intestine. Bacteria in the colonic lumen then convert conjugated and hydrophilic bile acids to unconjugated, hydrophobic bile acids such as deoxycholic acid and lithocholic acid (Figure 1). These hydrophobic bile acids, deoxycholic acid in particular, have been reported to be multiple stress inducers and at high physiologic levels can create chaos within colon epithelial cells. These stresses include membrane perturbation, oxidative DNA damage, decrease in DNA repair proteins, mitotic stress, micronuclei formation, mitochondrial damage (metabolic stress) and endoplasmic reticulum (ER) stress (Figure 2).

Bottom Line: Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis.The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy.Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona, USA.

ABSTRACT
Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.

No MeSH data available.


Related in: MedlinePlus