Inter-individual variability in drug response is a significant clinical concern and may lead to the development of adverse drug reactions, which are currently a top-ten cause of death in the United States. Recently, the manifestation of disease, which may alter normal physiological function, has gained increased attention for its role as a contributing factor in the development of inter-individual responses to drugs. One such disease, known as nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease in Western society and represents a spectrum of clinical morbidities that range from the usually benign simple fatty liver to the more advanced nonalcoholic steatohepatitis (NASH). Prior investigations have identified liver-specific alterations in xenobiotic transporter and metabolizing enzymes in NASH, which lead to the functional disruption of drug disposition. To identify a useful model(s) that is representative of hepatic transporter expression profiles in humans with NASH, gene and protein expression profiles of liver membrane transporters were assayed across several commonly used experimental rodent models of the disease. NASH models that were representative of the human condition developed global, adaptive changes in transporter regulation in the liver, which was not present in models that failed to recapitulate human profiles. Specifically, decreased expression of hepatic uptake transporters was coupled with an induction of efflux transporters, which may serve as a hepatoprotective response by limiting hepatic exposure to potentially harmful substances during times of tissue stress. To link a possible molecular mechanism for these hepatic adaptations in NASH, the role of the oxidative stress-activated transcription factor, Nrf2, was investigated. A functional Nrf2 regulatory element was identified within the eighth intron of the human ABCC3 transporter gene, implicating Nrf2 activation in NASH as a contributor to the coordinated induction of hepatic efflux transporters in the disease. To further clarify the effects of NASH on renal membrane transporter regulation, a thorough analysis of gene and protein expression was conducted with the validated rodent models used previously. Following the manifestation of disease, a global induction of renal efflux was observed, suggesting a compensatory, coordinated response of membrane transporters in the kidney upon disease induction. The functional consequences of liver and kidney xenobiotic transporter dysregulation was shown to disrupt the disposition of the environmental toxicant, arsenic. Specifically, NASH results in increased excretion of arsenic into urine as well as altered hepatic and renal exposure. These findings are associated with hepatic and renal transporter dysregulation and demonstrate for the first time that NASH alters the disposition of environmental toxicants. In summary, these studies contribute novel findings that identify liver and kidney-specific adaptations in disease that may contribute to global alterations in xenobiotic disposition thereby increasing the likelihood of developing adverse drug reactions in patients with NASH.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/333487 |
| Date | January 2014 |
| Creators | Jimenez-Canet, Mark |
| Contributors | Cherrington, Nathan J., Cherrington, Nathan J., Gandolfi, A. Jay, Klimecki, Walter T., Vaillancourt, Richard R., Wright, Stephen H. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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