Bile-acid-induced cell injury and protection.
Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids (BAs) in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyl-N-methylglycine or cholylsarcosine, have also aroused pharmacological interest owing to their protective properties.
Perez
Maria-J
MJ
Department of Biochemistry and Molecular Biology Campus Miguel de Unamuno E.D. 129, Salamanca, Spain. mjperez@usal.es
Briz
Oscar
O
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001660:Biliary Tract Diseases / Q000503:physiopathology; D002462:Cell Membrane / Q000187:drug effects; D002779:Cholestasis / Q000378:metabolism; D019610:Cytoprotection / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D015394:Molecular Structure; D018384:Oxidative Stress
D001647:Bile Acids and Salts