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Carl A Goresky - One of the best experts on this subject based on the ideXlab platform.

  • Microsomal specificity underlying the differing hepatic formation of Bilirubin Glucuronide and glucose conjugates by rat and dog.
    Hepatology, 2005
    Co-Authors: U Sommerer, Ellen R. Gordon, Carl A Goresky
    Abstract:

    : Bilirubin monoGlucuronide monoglucoside diester is one of the principal Bilirubin conjugates in dog bile (and a lesser conjugate, in human bile), and Bilirubin diglucoside is an occasional trace conjugate in dog bile whereas, in contrast, neither is detectable in rat bile. In order to investigate, in comparative fashion, the factors underlying the formation of Glucuronide and glucose-containing conjugates, hepatic microsomes were isolated by differential centrifugation from the livers of both normal mongrel dogs and Sprague-Dawley rats, and their formation of Bilirubin conjugates examined, in the presence of varying levels of UDP-glucuronate and UDP-glucose. Bilirubin and its conjugates were extracted and separated by high-performance liquid chromatography; a new methodology was devised, which clearly separates Bilirubin diglucoside from Bilirubin monoGlucuronide, as well as Bilirubin diGlucuronide, the mixed monoGlucuronide monoglucoside conjugate and Bilirubin monoglucoside. At Bilirubin levels of 12.5 microM, in the presence of equal amounts of both UDP-glucuronate and UDP-glucose, dog microsomes formed substantial amounts of both Bilirubin diGlucuronide and the mixed monoGlucuronide-monoglucoside conjugate, and minor amounts of Bilirubin monoGlucuronide and Bilirubin diglucoside. Microsomes from rat liver, under similar conditions, formed only Bilirubin diGlucuronide and Bilirubin monoGlucuronide. When only UDP-glucose was present, dog microsomes formed predominantly diglucoside and rat, predominantly monoglucoside. The findings imply that it is not the availability of the UDP-glycoside but rather the preference of the microsomal enzymic system for the different glycosidic nucleotides which dictates the varieties of Bilirubin conjugates ordinarily formed in these two species.

Yuji Tanaka - One of the best experts on this subject based on the ideXlab platform.

  • oxidative and electrophilic stress induces multidrug resistance associated protein transporters via the nuclear factor e2 related factor 2 transcriptional pathway
    Hepatology, 2007
    Co-Authors: Jonathan M. Maher, Matthew Z. Dieter, Lauren M. Aleksunes, Angela L. Slitt, Grace L. Guo, Yuji Tanaka, George L. Scheffer, Jefferson Y. Chan, José E. Manautou
    Abstract:

    Multidrug resistance–associated proteins (Mrps) are adenosine triphosphate–dependent transporters that efflux chemicals out of cells. In the liver, Mrp2 transports Bilirubin-Glucuronide, glutathione (GSH), and drug conjugates into bile, whereas Mrp3 and Mrp4 efflux these entities into blood. The purpose of this study was to determine whether oxidative conditions (that is, the disruption of hepatic GSH synthesis) or the administration of nuclear factor-E2–related factor-2 (Nrf2) activators (oltipraz and butylated hydroxyanisole) can induce hepatic Mrp transporters and whether that induction is through the Nrf2 transcriptional pathway. Livers from hepatocyte-specific glutamate-cysteine ligase catalytic subunit–null mice had increased nuclear Nrf2 levels, marked gene and protein induction of the Nrf2 target gene NAD(P)H:quinone oxidoreductase 1, as well as Mrp2, Mrp3, and Mrp4 expression. The treatment of wild-type and Nrf2-null mice with oltipraz and butylated hydroxyanisole demonstrated that the induction of Mrp2, Mrp3, and Mrp4 is Nrf2-dependent. In Hepa1c1c7 cells treated with the Nrf2 activator tert-butyl hydroquinone, chromatin immunoprecipitation with Nrf2 antibodies revealed the binding of Nrf2 to antioxidant response elements in the promoter regions of mouse Mrp2 [−185 base pairs (bp)], Mrp3 (−9919 bp), and Mrp4 (−3767 bp). Conclusion: The activation of the Nrf2 regulatory pathway stimulates the coordinated induction of hepatic Mrps. (HEPATOLOGY 2007.)

  • increased renal expression of Bilirubin Glucuronide transporters in a rat model of obstructive jaundice
    American Journal of Physiology-gastrointestinal and Liver Physiology, 2002
    Co-Authors: Yuji Tanaka, Yoshinao Kobayashi, Esteban C Gabazza, Kunihiro Higuchi, Toshinori Kamisako, Makoto Kuroda, Keisuke Takeuchi, Motoh Iwasa, Masahiko Kaito, Yukihiko Adachi
    Abstract:

    Regulation of Bilirubin Glucuronide transporters during hyperBilirubinemia in hepatic and extrahepatic tissues is not completely clear. In the present study, we evaluated the regulation of the bili...

Yukihiko Adachi - One of the best experts on this subject based on the ideXlab platform.

Irwin M Arias - One of the best experts on this subject based on the ideXlab platform.

  • Rapid Publication Two Distinct Mechanisms for Bilirubin Glucuronide Transport by Rat Bile Canalicular Membrane Vesicles Demonstration of Defective ATP-dependent Transport in Rats (TR-)
    2016
    Co-Authors: Inherited Conjugated Hyperbilirubinemia, Toshirou Nishida, Zenaida Gatmaitan, Jayanta Roy-chowdhry, Irwin M Arias
    Abstract:

    Bilirubin is conjugated with glucuronic acid in hepatocytes and subsequently secreted in bile. The major conjugate is Bilirubin diGlucuronide. Using sealed vesicles which are primarily de-rived from the canalicular (CMV) and sinusoidal (SMV) membrane vesicle domains of the plasma membrane of hepato-cytes, we demonstrated that Bilirubin Glucuronides are trans-ported byCMV by both ATP- and membrane potential-depen-dent transport systems. In CMV from normal rats, these pro-cesses are additive. In CMV from TR- rats, which have an autosomal recessively inherited defect in biliary secretion of nonbile acid organic anions, ATP-dependent transport of biliru-bin diGlucuronide was absent whereas the membrane potential driven system was retained. Other canalicular ATP-dependent transport systems, which were previously described for organic cations and bile acids, are functionally retained in TR- rats. Our study indicates that Bilirubin Glucuronides are primarily secreted into the bile canaliculus by an ATP-dependent mecha-nism which is defective in an animal model ofthe human Dubin-Johnson syndrome. (J. Clin. Invest. 1992.90:2130-2135.) Key words: ATP-dependent transport * Bilirubin Glucuronides * cana-licular transport * inheritable jaundice (Dubin-Johnson syn-drome

  • Two distinct mechanisms for Bilirubin Glucuronide transport by rat bile canalicular membrane vesicles. Demonstration of defective ATP-dependent transport in rats (TR-) with inherited conjugated hyperBilirubinemia.
    Journal of Clinical Investigation, 1992
    Co-Authors: Toshirou Nishida, Jayanta Roy-chowdhry, Zenaida Gatmaitan, Irwin M Arias
    Abstract:

    Bilirubin is conjugated with glucuronic acid in hepatocytes and subsequently secreted in bile. The major conjugate is Bilirubin diGlucuronide. Using sealed vesicles which are primarily derived from the canalicular (CMV) and sinusoidal (SMV) membrane vesicle domains of the plasma membrane of hepatocytes, we demonstrated that Bilirubin Glucuronides are transported by CMV by both ATP- and membrane potential-dependent transport systems. In CMV from normal rats, these processes are additive. In CMV from TR- rats, which have an autosomal recessively inherited defect in biliary secretion of nonbile acid organic anions, ATP-dependent transport of Bilirubin diGlucuronide was absent whereas the membrane potential driven system was retained. Other canalicular ATP-dependent transport systems, which were previously described for organic cations and bile acids, are functionally retained in TR- rats. Our study indicates that Bilirubin Glucuronides are primarily secreted into the bile canaliculus by an ATP-dependent mechanism which is defective in an animal model of the human Dubin-Johnson syndrome.

  • Two Distinct Mechanisms for Bilirubin Glucuronide Transport by Rat Bile Canalicular Membrane Vesicles
    1992
    Co-Authors: Toshirou Nishida, Irwin M Arias, Zenaida Gatmaitan, Jayanta Roy-chowdhry, Marion Bessin
    Abstract:

    Bilirubin is conjugated with glucuronic acid in hepatocytes and subsequently secreted in bile. The major conjugate is Bilirubin diGlucuronide. Using sealed vesicles which are primarily derived from the canalicular (CMV) and sinusoidal (SMV) membrane vesicle domains ofthe plasma membrane ofhepatocytes, we demonstrated that Bilirubin Glucuronides are transported byCMV by both ATP- and membrane potential-dependent transport systems. InCMV from normal rats, these processes are additive. In CMV from TR- rats, which have an autosomal recessively inherited defect in biliary secretion of nonbile acid organic anions, ATP-dependent transport ofBilirubin diGlucuronide was absent whereas the membrane potential driven system was retained. Other canalicular ATP-dependent transport systems, which were previously described for organic cations and bile acids, are functionally retained in TR- rats. Our study indicates that Bilirubin Glucuronides are primarily secreted into the bile canaliculus by an ATP-dependent mechanism which is defective in an animal model ofthehuman DubinJohnson syndrome. (J. Clin. Invest. 1992.90:2130-2135.) Key words: ATP-dependent transport * Bilirubin Glucuronides* canalicular transport * inheritable jaundice (Dubin-Johnson syn

U Sommerer - One of the best experts on this subject based on the ideXlab platform.

  • Microsomal specificity underlying the differing hepatic formation of Bilirubin Glucuronide and glucose conjugates by rat and dog.
    Hepatology, 2005
    Co-Authors: U Sommerer, Ellen R. Gordon, Carl A Goresky
    Abstract:

    : Bilirubin monoGlucuronide monoglucoside diester is one of the principal Bilirubin conjugates in dog bile (and a lesser conjugate, in human bile), and Bilirubin diglucoside is an occasional trace conjugate in dog bile whereas, in contrast, neither is detectable in rat bile. In order to investigate, in comparative fashion, the factors underlying the formation of Glucuronide and glucose-containing conjugates, hepatic microsomes were isolated by differential centrifugation from the livers of both normal mongrel dogs and Sprague-Dawley rats, and their formation of Bilirubin conjugates examined, in the presence of varying levels of UDP-glucuronate and UDP-glucose. Bilirubin and its conjugates were extracted and separated by high-performance liquid chromatography; a new methodology was devised, which clearly separates Bilirubin diglucoside from Bilirubin monoGlucuronide, as well as Bilirubin diGlucuronide, the mixed monoGlucuronide monoglucoside conjugate and Bilirubin monoglucoside. At Bilirubin levels of 12.5 microM, in the presence of equal amounts of both UDP-glucuronate and UDP-glucose, dog microsomes formed substantial amounts of both Bilirubin diGlucuronide and the mixed monoGlucuronide-monoglucoside conjugate, and minor amounts of Bilirubin monoGlucuronide and Bilirubin diglucoside. Microsomes from rat liver, under similar conditions, formed only Bilirubin diGlucuronide and Bilirubin monoGlucuronide. When only UDP-glucose was present, dog microsomes formed predominantly diglucoside and rat, predominantly monoglucoside. The findings imply that it is not the availability of the UDP-glycoside but rather the preference of the microsomal enzymic system for the different glycosidic nucleotides which dictates the varieties of Bilirubin conjugates ordinarily formed in these two species.