Specific, metabolism-driven transporters in excretory epithelia and barrier tissues play a major role in determining xenobiotic uptake, distribution and excretion. Along with xenobiotic metabolizing enzymes, these transporters are our first defense against chemical toxins. We use comparative models (renal proximal tubules and hepatocytes from lower vertebrates and invertebrates, mammalian cells in culture derived from kidney and choroid plexus and isolated brain microvessels) in combination with confocal microscopy, intracellular microinjection and isolated membrane vesicle techniques to define the cellular mechanisms that drive xenobiotic transport. Recent progress has been in three areas. We have demonstrated vesicle mediated and microtubule-dependent events in the transcellular transport of organic anions and organic cations in renal proximal tubule, liver and choroid plexus. These results suggest that xenobiotic transport across the cell interior can involve mechanisms other than simple diffusion. We have demonstrated that ATP-driven xenobiotic pumps, p-glycoprotein and Mrp2, drive renal excretory transport of several drugs, including immunosuppresants, polypeptides and HIV protease inhibitors. The HIV protease inhibitors, saquinavir and ritonavir interacted with both p-glycoprotein and Mrp2 and ritonavir was the most potent inhibitor of these transporters of any drug tested, suggesting uses outside of AIDS therapy, e.g., reversal of drug resistance. Finally, we have begun to investigate mechanisms of xenobiotic transport in brain capillaries. We have developed a procedure to isolate intact brain capillaries with extended viability and have used the preparation to obtain molecular and functional evidence for active transport from brain to blood mediated by both p-glycoprotein and Mrp2. - epithelia, hepatocytes, xenobiotics, pollutant metabolites, kidney, blood-brain barrier, transport
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