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

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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 (maternal-fetal barrier, blood-brain barrier, blood-cerebral 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.