The mechanisms of active inorganic and organic solute transport and passive water movement that underlie bile formation and other critical hepatocellular functions are not clearly understood. Until recently, methods of study that have been responsible for the exponential increase in our understanding of transport phenomena in other epithelia had not been fully adapted to studies of hepatic transport. The proposed work seeks to identify and characterize membrane transport processes present in hepatocytes with an aim towards a better understanding of the mechanisms of bile formation and the pathophysiologic events that lead to cholestasis. Moreover, the relationship of specific transport mechanisms to other hepatocellular functions will be examined. Ion permeability and transport characteristics of rat liver plasma membrane vesicles derived from sinusoidal and canalicular domains will be studied, with particular emphasis on electrogenic Na:HCO3 transport, the sinusoidal Na:H antiport and canalicular C1:HCO3 exchange, transport processes proposed to be critically involved in a variety of hepatocellular functions, including bile formation and cell growth. With respect to bile formation, in vivo and in vitro models will be used to study specific effects of choleretic and cholestatic agents, including bile acids glucocorticoids, ethinyl estradiol, and thyroid hormone, on ion transport and permeability as well as the time course of these effects. The physiologic relevance of certain results will be further evaluated by comparison with studies on bile formation in the isolated perfused rat liver, using agents known to inhibit of stimulate specific transport processes. With respect to cell growth, the role of specific transport processes in hepatic regeneration following partial hepatectomy will be addressed using a recently described membrane vesicle preparation derived from partially hepatectomized rats and isolated perfused livers as experimental models. Vesicle transport in all sections of the proposal will be studied by radioactive tracer uptake measurements using a rapid-filtration technique. Ion permeability will be monitored with a calibrated, potential-sensitive carbocyanine dye. Isolated livers will be perfused with and erythrocyte-free solution in a previously validated recirculating system.
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