Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct.The absorption,distribution and elimination of drugs are impaired during this pa...Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct.The absorption,distribution and elimination of drugs are impaired during this pathology.Prolonged cholestasis may alter both liver and kidney function.Lactam antibiotics,diuretics,non-steroidal anti-inflammatory drugs,several antiviral drugs as well as endogenous compounds are classified as organic anions.The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds.It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions.The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis,such as multidrug resistanceassociated protein 2,organic anion transporting polypeptide 1,organic anion transporter 3,bilitranslocase,bromosulfophthalein/bilirubin binding protein,organic anion transporter 1 and sodium dependent bile salt transporter.The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.展开更多
The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular t...The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular transporters:multidrug resistance protein 1(MDR1, ABCB1),also known as P-glycoprotein,multidrug resistance-associated protein 2(MRP2,ABCC2),and the breast cancer resistance protein(BCRP,ABCG2).Their activities depend on regulation of expression and proper localization at the canalicular membrane,as regulated by transcriptional and post-transcriptional events,respectively.At transcriptional level,specific nuclear receptors(NR)s modulated by ligands,co-activators and co-repressors,mediate the physiological requirements of these transporters.This complex system is also responsible for alterations occurring in specific liver pathologies.We briefly describe the major ClassⅡNRs, pregnane X receptor(PXR)and constitutive androstane receptor(CAR),and their role in regulating expression of multidrug resistance proteins.Several therapeutic agents regulate the expression of relevant drug transporters through activation/inactivation of these NRs.We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition,involve CAR or PXR as mediators.展开更多
Bile acids(BAs)are originally known as detergents essential for the digestion and absorption of lipids.In recent years,extensive research has unveiled new functions of BAs as gut hormones that modulate physiological a...Bile acids(BAs)are originally known as detergents essential for the digestion and absorption of lipids.In recent years,extensive research has unveiled new functions of BAs as gut hormones that modulate physiological and pathological processes,including glucose and lipid metabolism,energy expenditure,inflammation,tumorigenesis,cardiovascular disease,and even the central nervous system in addition to cholesterol homeostasis,enterohepatic protection and liver regeneration.BAs are closely linked with gut microbiota which might explain some of their crucial roles in organs.The signaling actions of BAs can also be mediated through specific nuclear receptors and membranebound G protein-coupled receptors.Several pharmacological agents or bariatric surgeries have demonstrated efficacious therapeutic effects on metabolic diseases through targeting BA signaling.In this mini-review,we summarize recent advances in bile-ology,focusing on its translational studies.展开更多
基金Supported by Grants from FONCYT(PICT 2007,No.00966, PICT 2010,No.2127)CONICET(PIP 2009-2011,No.1665, PIP2012-2015,No.00014)UNR PID(2008-2011/2012-2015)
文摘Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct.The absorption,distribution and elimination of drugs are impaired during this pathology.Prolonged cholestasis may alter both liver and kidney function.Lactam antibiotics,diuretics,non-steroidal anti-inflammatory drugs,several antiviral drugs as well as endogenous compounds are classified as organic anions.The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds.It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions.The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis,such as multidrug resistanceassociated protein 2,organic anion transporting polypeptide 1,organic anion transporter 3,bilitranslocase,bromosulfophthalein/bilirubin binding protein,organic anion transporter 1 and sodium dependent bile salt transporter.The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.
基金Grants from Agencia Nacional de Promoción Científicay Tecnológica (PICT N° 05-26306)Consejo Nacional de Investigaciones Científicasy Técnicas (PIP N° 6442)Universidad Nacional de Rosario,Argentina
文摘The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular transporters:multidrug resistance protein 1(MDR1, ABCB1),also known as P-glycoprotein,multidrug resistance-associated protein 2(MRP2,ABCC2),and the breast cancer resistance protein(BCRP,ABCG2).Their activities depend on regulation of expression and proper localization at the canalicular membrane,as regulated by transcriptional and post-transcriptional events,respectively.At transcriptional level,specific nuclear receptors(NR)s modulated by ligands,co-activators and co-repressors,mediate the physiological requirements of these transporters.This complex system is also responsible for alterations occurring in specific liver pathologies.We briefly describe the major ClassⅡNRs, pregnane X receptor(PXR)and constitutive androstane receptor(CAR),and their role in regulating expression of multidrug resistance proteins.Several therapeutic agents regulate the expression of relevant drug transporters through activation/inactivation of these NRs.We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition,involve CAR or PXR as mediators.
基金Project supported by the National Cancer Institute(No.2R01CA139158)John Hench Foundation to Wen-dong HUANGthe National Natural Science Foundation of China(Nos.81471084 and 81773793)to Li-hua JIN
文摘Bile acids(BAs)are originally known as detergents essential for the digestion and absorption of lipids.In recent years,extensive research has unveiled new functions of BAs as gut hormones that modulate physiological and pathological processes,including glucose and lipid metabolism,energy expenditure,inflammation,tumorigenesis,cardiovascular disease,and even the central nervous system in addition to cholesterol homeostasis,enterohepatic protection and liver regeneration.BAs are closely linked with gut microbiota which might explain some of their crucial roles in organs.The signaling actions of BAs can also be mediated through specific nuclear receptors and membranebound G protein-coupled receptors.Several pharmacological agents or bariatric surgeries have demonstrated efficacious therapeutic effects on metabolic diseases through targeting BA signaling.In this mini-review,we summarize recent advances in bile-ology,focusing on its translational studies.
