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.
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