Characterization of P-glycoprotein expression as a multixenobiotic resistance mechanism in fish
Bard, Shannon Mala
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Transmembrane P-glycoproteins (P-gps) are responsible for multidrug resistance (MDR) phenotypes in tumor cell lines. P-glycoproteins function as energy dependent efflux flippases that prevent the cellular accumulation of a wide variety of compounds. We characterized P-gp expression in populations of several fish species exposed in their natural habitat to environmental contaminants which may be P-gp substrates/inducers. We evaluated whether P-gp activity may be implicated in this multixenobiotic resistant phenotype. In winter flounder (Pleuronectes americanus) with contaminant-associated liver tumors, P-gp was highly expressed in bile canaliculi of non-tumorous liver surrounding cholangiocellular carcinoma, but was not detected within tumors. Cellular stress caused by impaired bile elimination may be responsible for elevated P-gp. Killifish (Fundulus heteroclitus) from a contaminated field sites had higher intestinal P-gp and lower hepatic P-gp than control killifish. In contaminated fish, elevated intestinal P-gp may provide a barrier against absorption of P-gp substrates/inducers thus limiting the amount of these compounds exported to the liver. We investigated whether P-gp might be involved in induction of cytochrome P4501A (CYPIA). Although CYPIA and P-gp were both elevated in oil exposed blennies (Anoplarchus purpurescens), there was no induction of P-gp in blennies exposed to ß-naphthoflavone nor in killfish exposed to 2,3,7,8-tetrachlorodibenzofuran, both CYPIA inducer. Thus in fish, P-gp expression is not regulated by the aryl hydrocarbon receptor pathway. We developed a protocol for an in vivo assay to simultaneously evaluate P-gp mediated transport of a model substrate, rhodamine B (rhB), in multiple organs of killifish. Our results indicate that P-gps play a major role in transport of xenobiotics in fish especially in liver, brain, and ovary. Using this assay, we assessed whether the common environmental contaminant and carcinogen benzo(a)pyrene (B[a]P) is a P-gp substrate. We show that B[a]P and/or its CYP1A metabolites are not transported by P-gp in liver, brain, or ovary.
Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution October 2000
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