Different pathways of canalicular secretion of sulfated and non-sulfated fluorescent bile acids: a study in isolated hepatocyte couplets and TR− rats (original) (raw)
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Bile Acids in Physiology, Pathology and Pharmacology
Current Drug Metabolism, 2015
Bile acids, synthesized by hepatocytes from cholesterol, are specific and quantitatively important organic components of bile, where they are the main driving force of the osmotic process that generates bile flow toward the canaliculus. The bile acid pool comprises a variety of species of amphipathic acidic steroids. They are not mere detergent molecules that play a key role in fat digestion and the intestinal absorption of hydrophobic compounds present in the intestinal lumen after meals, including liposoluble vitamins. They are now known to be involved in the regulation of multiple functions in liver cells, mainly hepatocytes and cholangiocytes, and also in extrahepatic tissues. The identification of nuclear receptors, such as farnesoid X receptor (FXR or NR1H4), and plasma membrane receptors, such as the G protein-coupled bile acid receptor (TGR5, GPBAR1 or MBAR), which are able to trigger specific and complex responses upon activation (with dissimilar sensitivities) by different bile acid molecular species and synthetic agonists, has opened a new and promising field of research whose implications extend to physiology, pathology and pharmacology. In addition, pharmacological development has taken advantage of advances in the understanding of the chemistry and biology of bile acids and the biological systems that interact with them, which in addition to the receptors include several families of transporters and export pumps, to generate novel bile acid derivatives aimed at treating different liver diseases, such as cholestasis, biliary diseases, metabolic disorders and cancer. This review is an update of the role of bile acids in health and disease.
Bile acid transport across the hepatocyte canalicular membrane
The FASEB Journal
Transport of bile acids across the canalicular membrane of the hepatocyte provides the primary motive force for generation of bile flow and is rate limiting in the vectorial movement of bile acids from blood to bile. Several distinct carriers for bile acids have been defined based on physiological studies in isolated hepatocytes, membrane vesicles, hepatocyte couples, and the perfused rat liver including membrane potential-driven and ATP-dependent mechanisms. Several groups have isolated and functionally reconstituted a canalicular bile acid transport protein of M(r) approximately 110 kDa. The ATP-dependent mechanism for secretion of monovalent bile acids appears to be mediated by a yet to be identified protein of the ATP binding cassette family of transporters. However, it remains conjectural whether the ATP-dependent and membrane potential-driven components of canalicular bile acid transport are mediated by one or more transport proteins. Bile acid sulfates and glucuronides are substrates for the canalicular multispecific organic anion transporter whose activity has recently been associated with the multidrug resistance-associated protein.
Transport of bile acids in a human intestinal epithelial cell line, Caco-2
Biochimica et Biophysica Acta (BBA) - General Subjects, 1990
The transport of tanrocholic acid (TA) across Caco-2 cell monolayers was dependent on time in culture and reached a plateau after 28 days, at which time the apical (AP)-to-basolateral (131,) transport was 10-times greater than BL-to-AP transport. The amounts of TA inside the cells following application of 10 nM [I4C]TA to tile AP or BL side of the monolayers (30 min) were approximately equal (54.4 + 2.7 and 64.6 ± 2.8 fmol/mg protein, respectively). AP-to-BL transport of TA was saturable and temperature-dependent. Vm~ , and K m for transport were 13.7 pmol / mg protein per min and 49.7 pM, respectively. The transport of TA had an activation energy of 13.2 kcal-mo1-1, required Na + and glucose. AP-to-BL transport of |14C]TA was inhibited by the co-administration (on the AP side) of either unlabeled TA or deoxycholate, but it was not reduced by the presence of unlabeled TA on the BL side.
Transport of drugs in isolated hepatocytes the influence of bile salts
Biochemical Pharmacology, 1978
The influence of bile salts on hepatic transport of drugs was studied using isolated hepatocyte suspensions. Upra~e of the organic anions, dibromosulphthalein (DBSP), indcrcyanine green (ICG) and an organic cation, N4-acetyi procainamide ethobromide (APAEB) was measured. Afte; 60 min incubation the amount of DBSP, ICG and APAEB nresent in the cells was 17. 41 and 4.5 ner cent of the added amount respectively. The release of DBSP, ICG and APAEB from the hepatocytes preincubated with the agents under study, after 60 min incubation in fresh medium was 80.5, 12.5 and 48.9 per cent of the amount initially present respectively. The presence of bile canalicular membranes in the isolated hepatocytes was demonstrated by enzymehistochemistry: 5'nucleotidase activity showed sharp branched bands over the cell surface. When bile salts were present in the incubation medium. the cellular content of DBSP, ICG and APAEB was diminished. The taurocholate concentration which caused 50 per cent of the maximal effect was 0.07mM. O.lOmM and 0.06mM in experiments with DBSP, ICG and APAEB respectively. Pharmacokinetic analysis revealed that the influence of bile salts on cellular content of the three compounds was due to inhibition of the uptake into the isolated hepatocytes, rather than stimulation of release from the cells. The hypothesis, that stimulation of biliary output of organic anions in viw is due to a modifying effect of bile salts on the canalicular membranes. instead of being the result of the increased bile flow, is not supported by this study.
Quantitative relationship between bile acid structure and biliary lipid secretion in rats
Journal of Pharmaceutical Sciences, 1988
A series of unconjugated and taurine conjugated bile acids (BAS) differing in water solubility (SW,), critical micellar concentration (CMC), and hydrophilicity (K') were infused iv to rats at a tracer dose and a dose of 6 pmollminlkg over a 1-h period. Bile was collected for 3 h to evaluate the role of BA structure on cholesterol, phospholipids
An informal review of the author's five decades of research on the chemistry and biology of bile acids in health and disease is presented. The review begins with a discussion of bile acid structure and its remarkable diversity in vertebrates. Methods for tagging bile acids with tritium for metabolic or transport studies are summarized. Bile acids solubilize polar lipids in mixed micelles; progress in elucidating the structure of the mixed micelle is discussed. Extensive studies on bile acid metabolism in humans have permitted the development of physiological pharmacokinetic models that can be used to simulate bile acid metabolism. Consequences of defective bile acid biosynthesis and transport have been clarified, and therapy has been developed. Methods for measuring bile acids have been improved. The rise and fall of medical and contact dissolution of cholesterol gallstones is chronicled. Finally, principles of therapy with bile acid agonists and antagonists are given. Advances in understanding bile acid biology and chemistry have helped to improve the lives of patients with hepatobiliary or digestive disease.