Bile acids are the principal solid dissolved in bile. They play major roles in the formation of bile water, in the solubilization of bile lipids, and in the dispersion of the products of lipolysis in the gut lumen. During past years of grant support, we have studied bile acid metabolism in the developing organism. We have shown that such fundamental processes as bile acid synthesis, hepatic secretion, and intestinal absorption, are incompletely developed at birth and undergo maturation during the first weeks of life. In the grant period immediately preceding this application, we reexamined the bile acid constituents of human meconium. Meconium, the first feces of the newborn, contains the intestinal content of the fetus at birth, and, as such, is a record of intrauterine intestinal events. To our surprise, the bile acids of meconium proved to be a much more complex set than had previously been conceived. We identified several groups of short- chain bile acids, compounds which had largely been ignored in previous literature on bile acid metabolism. Although our analysis was limited to monohydroxylated bile acids (plus one dihydroxylated species), 10 to 15 previously unrecognized bile acids were identified. Certain of these were of major quantitative importance. Similar short-chain bile acids were identified in adult samples. In addition, preliminary studies suggested that glucuronidation was a major mechanism of short- chain bile acid metabolism, contrasting with the amino acid conjugation of conventional bile acids. During the projected grant period, problems raised by these findings will be pursued. We will broaden our identification of short-chain, and other atypical bile acids. Since the biological behavior of these compounds is largely unknown, we will further characterize their metabolism and turnover. We will prepare sets of bile acids with systematic variation in molecular configuration, and examine the influence of bile acid structure on function. We will perform a series of studies to begin to define the biosynthetic pathways of short-chain bile acid formation. Finally, we will further explore the role of glucuronidation in bile acid metabolism.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
7R01HD014198-13
Application #
3312524
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1979-08-01
Project End
1991-12-31
Budget Start
1989-09-01
Budget End
1989-12-31
Support Year
13
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Little, J M; Drake, R R; Vonk, R et al. (1995) Characterization of human liver microsomal UDP-glycosyltransferases using photoaffinity analogs. J Pharmacol Exp Ther 273:1551-9
Battaglia, E; Elass, A; Drake, R R et al. (1995) Characterization of a new class of inhibitors of the recombinant human liver UDP-glucuronosyltransferase, UGT1*6. Biochim Biophys Acta 1243:9-14
Radominska, A; Little, J M; Lester, R et al. (1994) Bile acid glucuronidation by rat liver microsomes and cDNA-expressed UDP-glucuronosyltransferases. Biochim Biophys Acta 1205:75-82
Radominska, A; Paul, P; Treat, S et al. (1994) Photoaffinity labeling for evaluation of uridinyl analogs as specific inhibitors of rat liver microsomal UDP-glucuronosyltransferases. Biochim Biophys Acta 1205:336-45
Radominska, A; Berg, C; Treat, S et al. (1994) Characterization of UDP-glucuronic acid transport in rat liver microsomal vesicles with photoaffinity analogs. Biochim Biophys Acta 1195:63-70
Radominska, A; Treat, S; Little, J (1993) Bile acid metabolism and the pathophysiology of cholestasis. Semin Liver Dis 13:219-34
Radominska, A; Little, J; Pyrek, J S et al. (1993) A novel UDP-Glc-specific glucosyltransferase catalyzing the biosynthesis of 6-O-glucosides of bile acids in human liver microsomes. J Biol Chem 268:15127-35
Panfil, I; Lehman, P A; Zimniak, P et al. (1992) Biosynthesis and chemical synthesis of carboxyl-linked glucuronide of lithocholic acid. Biochim Biophys Acta 1126:221-8
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
Radominska, A; Little, J M; Lester, R et al. (1992) Hepatic metabolism of 3-oxoandrost-4-ene-17 beta-carboxylic acid in the adult rat: formation of carboxyl-linked glucuronides both in vivo and in vitro. Steroids 57:328-34

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