Physiological function of P-glycoprotein in sanctuary tissue barriers in teleosts

点击翻译按钮获取中文摘要

The maintenance of appropriate concentrations of endogenously produced, and exogenously acquired, molecules is an essential regulatory function in organisms. Prevention of their over-accumulation can be achieved through chemical translocation across biological membranes by most members of the large ATP-binding cassette (ABC) gene family. In mammals, ABC efflux transporters show predominant expression in tissues involved in absorption (gastrointestinal tract), secretion/excretion (kidney), or those that constitute internal tissue boundaries, where they limit chemical uptake and penetration into sanctuary tissues (maternalfetal barrier, blood-brain barrier, bloodcerebral spinal fluid barrier, blood-testes barrier). The 170 kDa protein P-glycoprotein is a multi-chemical resistance transporter that confers multidrug resistance (MDR) to cancer cells and multixenobiotic resistance (MXR) to aquatic organisms. Very little information exists on P-gp function in various sanctuary tissues of fish including the barriers protecting the brain and gonads. Defining a common pharmacore, particularly for endogenous compounds in sanctuary tissues, is necessary to begin to understand P-gp function, and the resulting effects on endogenous chemical toxicokinetics in whole organisms. Equally limited, is information regarding P-gp regulation and signaling pathways for induction in these and other tissues. Whole organisms, isolated tissues and isolated cells will be used in experiments to examine the physiological significance of normal P-gp function (i.e. not involving xenobiotics) in several sanctuary tissues. The substrate base, constituitive protein levels and activity, induction, regulation and signaling pathways with regard to P-gp function will be examined in several sanctuary tissue barriers; these are the primary interfaces between the peripheral circulation and the CNS/gonads of vertebrates (blood-brain, blood-testes, blood-ovary barriers). This research has several aims: 1) to assess the physiological roles of P-gp in sanctuary tissues, 2) to elucidate the regulatory mechanisms underlying P-gp expression (and MRP transporters), 3) increase knowledge regarding the teleost P-gp endogenous substrate base in teleosts, 4) to determine if a relationship exists between P-gp and MRP regulation, and 5) to determine the functional significance of sanctuary tissue barriers in teleosts and the contributions made to it by P-gp. This novel research will have significance in several areas: 1) increase knowledge regarding chemical transport physiology in teleosts, 2) understand the relevance of transport physiology chemical ecology, ecotoxicology, and life history, 3) provide insight into the sanctuary tissue barriers , 4) facilitate a priori predictions regarding the toxicokinetics of endogenous and exogenous chemicals, and 5) aid in model development to facilitate the treatment of animal and human diseases in which these transporters play a major role.