Hepatobiliary disposition of 3alpha,6alpha,7alpha,12alpha-tetrahydroxy-cholanoyl taurine: a substrate for multiple canalicular transporters.

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Vandana MegarajMary Vore

Abstract

Tetrahydroxy bile acids become major biliary bile acids in Bsep(-/-) mice and Fxr(-/-) mice fed cholic acid; we characterized disposition of these novel bile acids that also occur in patients with cholestasis. We investigated mouse Mrp2 (mMrp2) and P-glycoprotein [(P-gp) mMdr1a]-mediated transport of a tetrahydroxy bile acid, 6α-OH-taurocholic acid (6α-OH-TC), and its biliary excretion in wild-type and Mrp2(-/-) mice in the presence or absence of N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), a P-gp and breast cancer resistance protein inhibitor. 6α-OH-TC was rapidly excreted into bile of wild-type mice (78% recovery); coinfusion of GF120918 had no significant effect. In Mrp2(-/-) mice, biliary excretion was decreased (52% recovery) and coinfusion of GF120918 further decreased these values (34% recovery). In wild-type, but not Mrp2(-/-), mice, 6α-OH-TC increased bile flow 2.5-fold. Membrane vesicle transport studies of 6α-OH-TC (0.05-0.75 mM) yielded saturation kinetics with a higher apparent affinity for mMrp2 (K(m) = 0.13 mM) than for mMdr1a (K(m) = 0.33 mM); mBsep transported 6α-OH-TC with positive cooperativity (Hill slope = 2.1). Huma...Continue Reading

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Citations

Mar 13, 2014·Acta Biochimica Et Biophysica Sinica·Xiali ZhangFusheng Wan
Nov 15, 2014·International Journal of Molecular Medicine·Xiali ZhangFusheng Wan
Jan 30, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Frans J C CuperusMichael Trauner
Jan 9, 2014·Molecular and Cellular Biochemistry·Eugene HrycayStelvio Bandiera
Oct 8, 2019·Critical Reviews in Toxicology·Neel DefermPieter Annaert
Jun 15, 2013·American Journal of Physiology. Gastrointestinal and Liver Physiology·Renxue WangVictor Ling
Mar 14, 2021·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Jonathan A ShepsVictor Ling
May 4, 2021·Frontiers in Cell and Developmental Biology·Xiaodan HouQiong Li

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