Our long term objectives are to clarify the relationships between clearance functions, cell constituents and structure of the liver. Our approach is to perturb the system with a model toxin, identify the early impairments in function and then determine if alterations in selected cell constituents underlie the early functional impairments. Development of canalicular injury in fasted rats after administration of 1,1-dichloroethylene (1,1-DCE) provides a useful in vivo model system to study the relationships between morphological changes in this liver compartment and impairments in hepatobiliary clearance because a) 1,1-DCE produces striking early alterations in bile canaliculi and b) fed rats are much less vulnerable to the hepatoxicity of 1,1-DCE than fasted rats. This fed-fasted difference allows changes in clearance functions which are injury-associated to be distinguished from changes which may be due to the metabolism of this xenobiotic. The proposed studies will be conducted in unanesthetized, unrestrained rats with previously implanted bile duct, jugular vein and portal vein cannulas.
Specific aims are: 1) Use marker solutes, endogenous when possible, to identify hepatobiliary clearance impairments which are associated with early canalicular injury. 2) Differentiate between impairments in uptake vs transport processes by pharmacokinetics and between focal vs centrolobular permeability changes by ultrastructure. 3) Determine if canalicular regurgitation or biliary leakiness could underlie the impaired solute clearance. 4) Determine if alterations in specific liver constituents, i.e., membrane ATPases (by histochemistry), nucleotides (by HPLC) or cytoskeletal constituents (by immunocytochemical staining), could underlie clearance impairments. These in vivo, time-course studies should clarify relationships between the development of canalicular injury and the functional integrity of major processes of bile formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK034806-03
Application #
3233052
Study Section
Pathology B Study Section (PTHB)
Project Start
1985-09-01
Project End
1989-08-31
Budget Start
1987-09-01
Budget End
1989-08-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Jones, Juliet A; Kaphalia, Lata; Treinen-Moslen, Mary et al. (2003) Proteomic characterization of metabolites, protein adducts, and biliary proteins in rats exposed to 1,1-dichloroethylene or diclofenac. Chem Res Toxicol 16:1306-17
Atchison, C R; West, A B; Balakumaran, A et al. (2000) Drug enterocyte adducts: possible causal factor for diclofenac enteropathy in rats. Gastroenterology 119:1537-47
Atchison, C R; Balakumaran, A; West, A B et al. (2000) Aging enhances susceptibility of diclofenac-treated rats to gastric ulceration, while attenuating enteropathy. Dig Dis Sci 45:614-20
Kanz, M F; Gunasena, G H; Kaphalia, L et al. (1998) A minimally toxic dose of methylene dianiline injures biliary epithelial cells in rats. Toxicol Appl Pharmacol 150:414-26
Woodard, S H; Moslen, M T (1998) Decreased biliary secretion of proteins and phospholipids by rats with 1,1-dichloroethylene-induced bile canalicular injury. Toxicol Appl Pharmacol 152:295-301
Moslen, M T; Kanz, M F; Bhatia, J et al. (1994) Biliary glutathione and some amino acids are markedly diminished when biliary pressure is elevated. Exp Mol Pathol 61:1-15
Moslen, M T; Kanz, M F (1993) Biliary excretion of marker solutes by rats with 1,1-dichloroethylene-induced bile canalicular injury. Toxicol Appl Pharmacol 122:117-30
Moslen, M T; Kanz, M F; Bhatia, J et al. (1992) Biliary endogenous inorganic phosphate, D-glucose, IgA and transferrin are differentially altered by hydrostatic pressure. J Hepatol 16:89-97
Kanz, M F; Whitehead, R F; Ferguson, A E et al. (1992) Biliary function studies during multiple time periods in freely moving rats. A useful system and set of marker solutes. J Pharmacol Toxicol Methods 27:7-15
Kanz, M F; Taj, Z; Moslen, M T (1991) 1,1-Dichloroethylene hepatotoxicity: hypothyroidism decreases metabolism and covalent binding but not injury in the rat. Toxicology 70:213-29

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