Characterization of P-glycoprotein expression as a multixenobiotic resistance mechanism in fish
Bard, Shannon Mala
MetadataShow full item record
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
Suggested CitationThesis: Bard, Shannon Mala, "Characterization of P-glycoprotein expression as a multixenobiotic resistance mechanism in fish", 2000-10, DOI:10.1575/1912/3537, https://hdl.handle.net/1912/3537
Showing items related by title, author, creator and subject.
Regulation of pregnane-X-receptor, CYP3A and P-glycoprotein genes in the PCB-resistant killifish (Fundulus heteroclitus) population from New Bedford Harbor Grans, Johanna; Wassmur, Britt; Fernandez-Santoscoy, María; Zanette, Juliano; Woodin, Bruce R.; Karchner, Sibel I.; Nacci, Diane E.; Champlin, Denise; Jayaraman, Saro; Hahn, Mark E.; Stegeman, John J.; Celander, Malin C. (2014-12)Killifish survive and reproduce in the New Bedford Harbor (NBH) in Massachusetts (MA), USA, a site severely contaminated with polychlorinated biphenyls (PCBs) for decades. Levels of 22 different PCB congeners were analyzed ...
Geomagnetic variations in the Northwest Atlantic : implications for the electrical resistivity of the oceanic lithosphere Poehls, Kenneth Allen (Massachusetts Institute of Technology and Woods Hole Oceanographic Institution, 1975-10)A geomagnetic variation study on mature oceanic lithosphere in the North Atlantic just south of Bermuda has revealed the presence of at least one layer of low electrical resistivity. The low resistivity layer of approximately ...
Characterization of resistance to halogenated aromatic hydrocarbons in a population of Fundulus heteroclitus from a marine superfund site Bello, Susan M. (Massachusetts Institute of Technology and Woods Hole Oceanographic Institution, 1999-09)New Bedford Harbor (NBH), MA, is contaminated with halogenated aromatic hydrocarbons HAH including some potent aryl hydrocarbon receptor AhR agonists. To determine if Fundulus heterocitus from NBH have developed resistance ...