The objectives of the proposed research are to characterize the mechanisms by which steroid D-ring glucuronides inhibit bile flow and bile acid secretion. The effect of the cholestatic glucuronides on Na+K+-ATPase activity and the binding of bile acids will be investigated in vitro in canalicular enriched fraction of plasma membranes to determine if there is a correlation with in vivo inhibition of bile acid independent and bile acid dependent flow respectively. The effects of pregnancy and chronic estrogen treatment on the metabolism and biliary excretion of drugs and model compounds will also be investigated. The model systems to be used are isolated rat hepatic plasma membranes, the isolated perfused rat liver and in vivo in the rat.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD013250-07
Application #
3312154
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1979-09-30
Project End
1986-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
7
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Vore, M; Liu, Y; Huang, L (1997) Cholestatic properties and hepatic transport of steroid glucuronides. Drug Metab Rev 29:183-203
Vore, M; Hoffman, T; Gosland, M (1996) ATP-dependent transport of beta-estradiol 17-(beta-D-glucuronide) in rat canalicular membrane vesicles. Am J Physiol 271:G791-8
Liu, Y; Huang, L; Hoffman, T et al. (1996) MDR1 substrates/modulators protect against beta-estradiol-17beta-D-glucuronide cholestasis in rat liver. Cancer Res 56:4992-7
Liu, Y; Ganguly, T; Hyde, J F et al. (1995) Prolactin increases mRNA encoding Na(+)-TC cotransport polypeptide and hepatic Na(+)-TC cotransport. Am J Physiol 268:G11-7
Ganguly, T C; Liu, Y; Hyde, J F et al. (1994) Prolactin increases hepatic Na+/taurocholate co-transport activity and messenger RNA post partum. Biochem J 303 ( Pt 1):33-6
Vore, M; Hoffman, T (1994) Carrier-mediated electrogenic transport of estradiol-17 beta-glucuronide in rat liver BMV. Am J Physiol 267:G546-51
Gosland, M; Tsuboi, C; Hoffman, T et al. (1993) 17 beta-estradiol glucuronide: an inducer of cholestasis and a physiological substrate for the multidrug resistance transporter. Cancer Res 53:5382-5
Ganguly, T; Hyde, J F; Vore, M (1993) Prolactin increases Na+/taurocholate cotransport in isolated hepatocytes from postpartum rats and ovariectomized rats. J Pharmacol Exp Ther 267:82-7
Liu, Y; Hyde, J F; Vore, M (1992) Prolactin regulates maternal bile secretory function post partum. J Pharmacol Exp Ther 261:560-6
Zimniak, P; Ziller 3rd, S A; Panfil, I et al. (1992) Identification of an anion-transport ATPase that catalyzes glutathione conjugate-dependent ATP hydrolysis in canalicular plasma membranes from normal rats and rats with conjugated hyperbilirubinemia (GY mutant). Arch Biochem Biophys 292:534-8

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