How we have learned about the complexity of physiology,pathobiology and pharmacology of bile acids and biliary secretion

During the last decades the concept of bile secretion as merely a way to add detergent components to the intestinal mixture to facilitate fat digestion/absorption and to eliminate side products of heme metabolism has evolved considerably. In the series of mini-reviews that the World Journal of Gastroenterology is to publish in its section of "Highlight Topics",we will intend to give a brief but updated overview of our knowledge in this fi eld. This introductory letter is intended to thank all scientists who have contributed to the development of this area of knowledge in gastroenterology.

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 involvingoxidative 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.

Bile acids:Chemistry,physiology,and pathophysiology

The family of bile acids includes a group of molecular species of acidic steroids with very peculiar physical-chemical and biological characteristics.They are synthesized by the liver from cholesterol through several complementary pathways that are controlled by mechanisms involving finetuning by the levels of certain bile acid species.Although their best-known role is their participation in the digestion and absorption of fat,they also play an important role in several other physiological processes.Thus,genetic abnormalities accounting for alterations in their synthesis,biotransformation and/or transport may result in severe alterations,even leading to lethal situations for which the sole therapeutic option may be liver transplantation.Moreover,the increased levels of bile acids reached during cholestatic liver diseases are known to induce oxidative stress and apoptosis,resulting in damage to the liver parenchyma and,eventually,extrahepatic tissues.When this occurs during pregnancy,the outcome of gestation may be challenged.In contrast,the physical-chemical and biological properties of these compounds have been used as the bases for the development of drugs and as pharmaceutical tools for the delivery of active agents.

Excretion of biliary compounds during intrauterine life

In adults,the hepatobiliary system,together with the kidney,constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine,respectively.However,during intrauterine life the biliary route of excretion for cholephilic compounds,such as bile acids and biliary pigments,is very poor.Although very early in pregnancy the fetal liver produces bile acids,bilirubin and biliverdin,these compounds cannot be efficiently eliminated by the fetal hepatobiliary system,owing to the immaturity of the excretory machinery in the fetal liver.Therefore,the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta.Owing to the presence of detoxifying enzymes and specifi c transport systems at different locations of the placental barrier,such as the endothe-lial cells of chorionic vessels and trophoblast cells,this organ plays an important role in the hepatobiliary-like function during intrauterine life.The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother.This may result in oxidative stress and apoptosis,mainly in the placenta and fetal liver,which might affect normal fetal development and challenge the fate of the pregnancy.The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem.