(Taken from application) Bile salts interact with cell and organelle membranes in hepatocytes, enterocytes, and biliary epithelial cells. Despite growing knowledge of the physical chemistry of bile, far less is known regarding bile salt interactions with membrane lipids. Bile salts act as a double edged sword: during cholestasis bile salts accumulate and are most likely a final common pathway by which further liver damage occurs; in the colon bile salts act as a co-carcinogen. Although certain hydrophilic bile salts such as ursodeoxycholate conjugates have been demonstrated to protect at the cellular level against the cytotoxic effects of hydrophobic bile salts, the mechanism by which this occurs in unknown. This proposal asks fundamental question of how detergent properties of bile salts and their mixtures alter the barrier function of cell membranes to potentially toxic agents such as calcium, and how cyptoprotective hydrophilic bile salts appear to ameliorate these effects. On the basis of preliminary data described herein, we propose two hypotheses: (1) monomeric aqueous concentrations of hydrophobic bile salts are cytotoxic because they can rapidly transport divalent cations across cellular membranes, independent of protein channels; and (2) the cytoprotective ability of hydrophilic bile salts depends not on intramembrane interactions, but on formation of simple micelles containing both hydrophobic and hydrophilic bile salts; hence, cytoprotection on a physical chemical basis occurs solely under conditions where simple micelles are present such as the canalicular membrane.
The specific aims of this proposal address two questions: How are hydrophobic bile salts toxic to membranes? How do hydrophilic bile salts act as cytoprotective agents? By comparison of physiologically composed model lipid systems with native membranes, we will determine the importance of bile salt-mediated increases in membrane permeability in physiological systems, and explore the physical-chemical basis of cytoprotection both at the level of the canalicular membrane and within the hepatocyte. We believe that elucidating physical-chemical mechanisms by which mixtures of hydrophilic and hydrophobic bile salts interact with membranes will allow an understanding of the cytotoxic and cytoprotective effects of bile salts, and provide a foundation for optimal design of other pharmacological agents to treat chronic cholestasis.
|Donovan, J M (1999) Physical and metabolic factors in gallstone pathogenesis. Gastroenterol Clin North Am 28:75-97|