Secondary bile acids: an underrecognized cause of colon cancer
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WORLD JOURNAL OF SURGICAL ONCOLOGY
REVIEW
Open Access
Secondary bile acids: an underrecognized cause of colon cancer Hana Ajouz, Deborah Mukherji and Ali Shamseddine*
Abstract Bile acids were first proposed as carcinogens in 1939. Since then, accumulated evidence has linked exposure of cells of the gastrointestinal tract to repeated high physiologic levels of bile acids as an important risk factor for gastrointestinal cancers. High exposure to bile acids may occur in a number of settings, but most importantly, is prevalent among individuals who have a high dietary fat intake. A rapid effect on cells of high bile acid exposure is the generation of reactive oxygen species and reactive nitrogen species, disruption of the cell membrane and mitochondria, induction of DNA damage, mutation and apoptosis, and development of reduced apoptosis capability upon chronic exposure. Here, we review the substantial evidence of the mechanism of secondary bile acids and their role in colon cancer.
Introduction Bile Acids (BA) are normal components of the lumenal contents of the gastrointestinal (GI) tract, where they enable absorption of lipids, cholesterol, and fat-soluble vitamins. In essence, they act as a physiologic detergent and regulator of intestinal epithelial homeostasis in the gastrointestinal tract [1]. However, BAs, specifically lithocholic acid (LCA) - a secondary BA - also constitute a rare example of toxic endobiotics [2]. In fact, BAs were first proposed as a potential tumor-promoting agent in 1939 [3]. At high physiologic concentrations, BAs can cause oxidative/nitrosative stress, DNA damage, apoptosis, and mutation [4]. Furthermore, frequently repeated and prolonged exposure of tissues to high physiological levels of BAs can lead to the generation of genomic instability, development of apoptosis resistance and, ultimately, cancer [4]. And since BAs are normal components of the luminal contents of the GI tract, finding the exact mechanism of their carcinogenic effect has become intriguing. Several factors have been found to increase levels of BAs: most importantly, a high dietary fat intake. Our aim is to explain the correlation between the concentration of fecal secondary BAs -mainly deoxycholic acid (DOC) and LCA - and the colorectal cancer incidence that * Correspondence: [email protected] Department of Hematology/Oncology, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
was highlighted by several epidemiological studies but whose molecular mechanism remain far from clear. Furthermore, BAs were also found to be etiologic agents of other GI tract cancers, namely that of the esophagus [5], stomach [6], small intestine [7], liver [8], pancreas [9] and biliary tract [10].
Review Biochemistry and physiology of secondary bile acids in the body
Primary BAs (cholic acid and chenodeoxycholic acid) are derived from cholesterol by a sequence of enzymatic reactions occurring mainly in the liver. Synthesis of a full complement of BAs requires 17 individual enzymes an
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