Regulation and functional significance of the ABC transporter P-glycoprotein (ABCB1) in fish

点击翻译按钮获取中文摘要

Organisms regulate endogenous and xenobiotic chemicals to reduce their accumulation and the potential for toxic effects. The mechanisms for chemical homeostasis include: 1) biotransformation to metabolites , 2) membrane efflux transport of metabolites , and 3) membrane efflux transport of unmetabolized parent compound (e.g. Phase III transport: P-glycoprotein [P-gp, ABCB family]). The transmembrane protein P-gp, is a chemical efflux transporter in the ATP-binding cassette (ABC) transport protein superfamily (ABCB1/MDR1). P-gp provides a multixenobiotic resistance mechanism (MXR) to contaminants in fish that is analogous to the multidrug resistance (MDR) mechanism found in mammals . MXR is a phenomenon of tremendous adaptational value for fish living in polluted environments that acts through an enhanced expression of P-gp which restricts xenobiotic uptake. In fish, P-gp is predominantly expressed in organs that have an excretion (e.g. liver), absorption (e.g. intestine), or barrier (e.g. blood brain barrier [BBB]) function. Although considerable information on P-gp in mammals has been generated in recent years, we still do not know how P-gp works as an efflux pump or what its roles are in physiology, although it is believed to be the only ABC transporter whose sole function is to protect cells against a wide range of chemicals. In mammals, P-gp transports a broad variety of compounds that include endogenous molecules, drugs, and environmental chemicals. In fish, the range of known substrates on which P-gp act is limited and appears to be different from mammals. Defining a common pharmacore for both substrates is necessary to begin to understand P-gp’s role in chemical toxicokinetics. This is particularly important when fish are exposed to both P-gp substrates and inhibitors in chemical mixtures; altered toxicokinetics may lead to increased accumulation of chemicals and the susceptibility to toxic effects. Very little information exists on the constitutive or inducible levels of P-gp following xenobiotic exposure in fish. Equally limited, is information regarding P-gp regulation or the signaling pathways involved in its induction. Limited evidence suggests that controls for the up-regulation of P-gp can occur in response to a number of signals, including specific xenobiotics, endogenous molecules, and stress. A newly emerging field of study concerns the roles of nuclear factors (e.g. Pregnane X receptor [PXR]) on P-gp expression. Common and coordinated signaling mechanisms may exist for xenobiotic metabolizing enzymes through pathways such as PXR. Well-established in vitro fish cell model systems and whole animals will be used to investigate the substrate base, P-gp levels, induction, regulation, and signaling pathways proposed/described above. The ecological and environmental significance of P-gp function at the whole organism level will investigated using the blood brain barrier (BBB) as a model tissue. The BBB is the primary interface between the peripheral circulation and the CNS of vertebrates. The molecular basis of the selective nature of the BBB includes P-gp that prevents some xenobiotics from entering the CNS. Very little information exists regarding the significance of the BBB in fish. The role P-gp plays in its function is an area of teleost physiology that is under researched. This research has several aims: 1) to assess the physiological and toxicological roles of P-gp in teleosts, 2) to elucidate the regulatory mechanisms underlying P-gp expression, 3) to increase knowledge regarding the teleost P-gp substrate base, 4) to determine if a relationship exists between P-gp and other chemical defense systems, and 5) to determine the functional significance of the BBB in fish and P-gp's role in it.