Date of Award

8-2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Environmental Toxicology

Advisor

Baldwin, William

Committee Member

Bain , Lisa

Committee Member

Rice , Charles

Committee Member

Watt , Paula

Committee Member

Klaine , Stephen

Abstract

The Constitutive Androstane Receptor (CAR) and the Pregnane X Receptor (PXR) are nuclear receptors of significant importance in the regulation of enzymes that metabolize, detoxify and eliminate compounds from the body. In this study we assessed the protective role of CAR and PXR in the basal and inducible regulation of Cytrochrome P450s (CYPs), and the potential of CAR and PXR to help protect individuals from the organophosphate, parathion and the plasticizer, nonylphenol, putatively due to improved metabolism and elimination. Knockout models of these receptors were used to model susceptible populations such as children that are known to have lower CAR and PXR expression during the first six months of age. A humanized model was used to extrapolate findings to human populations. Overall, the data suggests that individuals with low CAR or PXR (newborn children), or low CAR/PXR activation (elderly) may be more susceptible to xenobiotic toxicity putatively because of the lower expression of CAR and PXR resulting in a lower expression of CYPs which leads to the inability to metabolize, detoxify and eliminate toxic compounds.

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