The uptake of chemicals into hepatocytes and subsequent excretion into bile are mediated by membrane transport systems. These carriers are involved in removing endogenous and exogenous toxic chemicals from the blood thereby facilitating elimination from the body. A number of studies have indicated that exposure to numerous toxicants and several disease states can affect these transport systems. The long-term objectives of this research include isolation and characterization of the molecular entities involved in the transport of organic anions out of the hepatocyte across the canalicular membrane and into bile. In vivo data indicate that insulin-dependent diabetes alters the biliary clearance of several xenobiotic chemicals, but the mechanisms responsible for these changes are unknown. Because diabetes increases the synthesis and enterohepatic recirculation of bile acids and bile acids are known to interact with the organic anions transporter, the proposed studies will examine transporter kinetics in bile canalicular-enriched plasma membrane vesicles that are isolated from liver of normal, streptozotocin-induced diabetic without insulin treatment and insulin-treated diabetic rats. This project will answer the specific hypotheses: 1) is the decreased biliary bicarbonate in excretion due to altered properties of the canalicular chloride/bicarbonate transporter and 2) is the altered organic anion excretion due to an allosteric interaction of bile acids with the canalicular anion transporter. A proposed kinetic model describing the interactions between bile acids and organic anions will be refined. These kinetic studies of canalicular transport in diabetic rats will facilitate comprehension of the complex processes of hepatic elimination and may assist in the development of more effective drug therapy for diabetic patients.
