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A multi-level assessment of P-glycoprotein's role in fish: From protein to behaviour

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Thesis type
(Thesis) Ph.D.
Date created
P-glycoprotein (P-gp) is an ATP-binding cassette (ABC) transporter known to contribute to the efflux of unmodified xenobiotics from organisms' cells, playing an essential role in chemical defence. In aquatic organisms living in polluted environments, including fish, P-gp has been associated with the phenotype of multi-xenobiotic resistance (MRX). To better understand the role of P-gp in chemical defences and its contribution to MXR in fish, a series of studies at different levels of biological organization were conducted. Baseline and induced (by the fungicide clotrimazole [CTZ]) P-gp protein expression was assessed in various tissues of zebrafish (Danio rerio) and rainbow trout (Oncorhynchus mykiss). P-gp tissue distribution parallels that of mammals being expressed in excretory, absorptive, and sanctuary tissues and was found in the liver, kidney, intestine, and brain; CTZ induced P-gp protein levels by a maximum of 2.1-fold in the brain. The effects of P-gp induction on the toxicokinetics of the neurotoxicant and P-gp substrate ivermectin (IVM) were examined. IVM was rapidly distributed to tissues and distribution reflected perfusion and tissue lipid content. Highly perfused tissues like liver and kidney accumulate IVM quickly, while sanctuary tissues like brain and gonad accumulated it more slowly. P-gp induction with CTZ did not significantly alter IVM's tissue distribution or toxicokinetic parameters. P-gp significantly contributed to neuroprotection against IVM-generated behavior dysfunction since its inhibition increased fish sensitivity Fasting did not decrease the neuroprotection provided by P-gp against IVM. However, P-gp induction by CTZ did not increase that same neuroprotection, possibly due to the low levels of P-gp induction. P-gp contributes significantly to fish's neuroprotection, and its inhibition by chemosensitizers increases fish sensitivity to neurotoxicants, highlighting the risk imposed on fish exposed to chemical mixtures. P-gp transport capacity is maintained under dietary restriction, showing that chemical defences are prioritized in fish. Baseline P-gp levels may be working near maximal capacity, since its induction does not significantly increase its neuroprotective actions.
151 pages.
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Thesis advisor: Kennedy, Christopher
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