Characterization of the Molecular Mechanisms of Xenobiotic-Induced NRF2 Activation for Disease Prevention and Intervention

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is the master regulator of the cellular antioxidant response upon exposure to xenobiotics. In addition, NRF2 induces the expression of genes involved in drug metabolism, protein homeostasis, anabolic metabolism, inflammation, proliferation, and survival. Understanding the molecular mechanisms of xenobiotic-induced NRF2 activation is crucial to guiding treatments for disease prevention and intervention. On the one hand, NRF2 activation using chemopreventive compounds is an effective pharmacological strategy to protect against environmental insults, such as exposure to solar ultraviolet (UV) radiation or the metalloid arsenic, that cause toxicity and cancer. In the first part of this dissertation, the achiote-derived apocarotenoid bixin was characterized as a novel NRF2 activator. Bixin pre-treatment prevented solar UV-induced photodamage and hair graying in several mouse models. These results suggest that using bixin to activate NRF2 is a feasible strategy to prevent UV-induced skin alterations. On the other hand, prolonged activation of NRF2 has been linked to the pathogenesis of cancer and other diseases. Our laboratory previously described that the environmental toxicant and carcinogen arsenic blocked autophagy and caused non-canonical activation of NRF2. In the last part of this dissertation, the molecular alterations elicited by acute exposure to low levels of arsenic were further explored. It was determined that low-level arsenic does not generate reactive oxygen species, a paradigm shifting discovery in the arsenic field. Additionally, arsenic blocked autophagy and induced a mild and transient endoplasmic reticulum (ER) stress response, indicating that restoring protein homeostasis might be crucial for the treatment of arsenic-induced diseases.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Graduate College

Grantor dc:publisher

The University of Arizona.

Year dc:date.issued

2018

Author dc:creator

• Rojo de la Vega Guinea, Elisa Montserrat

Advisor dc:contributor.advisor

• Zhang, Donna D.

Committee members dc:contributor.committeemember

• Wondrak, Georg T.
• Ooi, Aikseng

• arsenic
• bixin
• cancer
• NRF2
• oxidative stress
• ultraviolet radiation

Statement dc: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.

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10150/627744

OAI identifier oai:identifier

oai:repository.arizona.edu:10150/627744