The long-term goal is to understand the molecular mechanism of hepatic uptake and systemic disposition of endogenous signaling molecules and xenobiotics. Organic anion transporting polypeptides (Oatps) transport a broad range of organic anions. The liver-specific transporter Oatp1b2 (in rodents) has hum an orthologs OATP1B1 and OATP1B3, which are responsible for hepatic uptake of a large number of chemicals. Studies of Oatp1b2-null mice clearly illustrate an essential role of Oatp1b2 in hepatic uptake of certain xenobiotics. Our recent data suggest that Oatp1b2-null mice have decreased hepatic uptake and increased circulating levels of certain important endogenous molecules, such as unconjugated hydrophilic bile acids, bilirubin, a peptide hormone cholecystokinin-8, and prostaglandin E2 (PGE2). Our preliminary studies indicate that Oatp1b2-null mice have unexpected difficulty in maintaining their body temperature during surgical experiments, but are protected from lipopolysaccharide-induced hypothermia and hyperalgesia. The objective of this proposal is to use Oatp1b2-null and heterozygous mice as well as in vitro cellular and liver uptake systems to elucidate the physiological function and gene-dosage effects of Oatp1b2 in hepatic uptake and systemic disposition of endogenous chemicals and xenobiotics. The central hypothesis is that Oatp1b2 is essential in hepatic uptake of unconjugated hydrophilic bile acids, cholecystokinin-8, and PGE2, which have thermoregulatory and immunomodulatory activities. Increases in circulating levels of these signaling molecules in Oatp1b2-null mice lead to alterations in inflammatory responses and thermoregulation. Results from studies in 5 specific aims will elucidate: 1) the importance of Oatp1b2 in hepatic uptake of bile acids;2) how alterations of pH and bile acids influence Oatp1b2-dependent and -independent hepatocyte uptake of unconjugated bilirubin;3) gene- dosage effects of Oatp1b2 on hepatic uptake and systemic disposition of peptide hormones, prostaglandins, organic dyes, and a peptide-analog anti-diabetic drug;4) the importance of Oatp1b2 in hepatic uptake and systemic disposition of PGE2 and its impact on febrile response;and 5) the mechanism of protection of Oatp1b2-null mice from lipopolysaccharide-induced syndrome. This study is novel, because it will elucidate the mechanisms of the exciting preliminary findings that loss of Oatp1b2 results in not only greatly decreased hepatic uptake of certain xenobiotics, but also marked alteration of circulating endogenous signaling molecules and physiological changes during surgical conditions and inflammatory stresses. This study is significant, because results from this study will provide novel knowledge regarding how the loss/decrease of a liver-specific importer Oatp1b2 (OATP1B1/1B3 in humans) decreases hepatic uptake and increases circulating essential endogenous chemicals (bilirubin, bile acids, peptide hormones, prostaglandins) and xenobiotics, resulting in altered physiology and pharmacokinetics/toxicokinetics.
Hepatic uptake is a fundamental phenomenon that is required for endogenous compounds and xenobiotics, such as drugs and environmental pollutants, to elicit biological events in the liver. Additionally, hepatic uptake is part of the process known as first pass metabolism which limits systemic exposure to xenobiotics absorbed from the intestine. Data from this study will greatly advance knowledge concerning the function of what is considered the most important hepatic uptake transporter, within the areas of physiology, pharmacology, and toxicology. Ultimately, this will aid in predicting human drug efficacy and safety, and promote the development of liver-specific drug delivery.
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