ABSTRACT
Introduction...................................................................................................... 349 Phase II Gene Induction: Role of Nrf2 Nuclear Translocation and Its Binding to the Antioxidant Response Element ............................... 350
Keap-1 and Its Role in Nrf2-Mediated Gene Expression ............................... 352 Stress Signaling Pathways That Induce Nrf2 Nuclear Translocation.............. 354 Theoretical Evidence of a-Lipoic Acid as an Inducer of Phase II Detoxification............................................................................................... 356
Experimental Evidence for a-Lipoic Acid as an Inducer of Nrf2 .................. 357 Future Directions for Research on Lipoic Acid and the Nrf2-Keap-1 System ..... 362 References ........................................................................................................ 365
Cells constantly encounter toxic electrophiles, mutagens, and oxidants that arise as by-products of normal metabolism and from the environment. Overlapping arrays of antioxidant and detoxification enzymes, collectively termed phase II detoxification enzymes, defend against both endogenous and exogenous insults. As might be expected from such an important collective defense system, phase II
enzymes are highly inducible. The transcription factor, NF E2-related factor 2 (Nrf2), is essential for induction of phase II defenses, as it is the principal regulatory protein for genes containing the antioxidant response element (ARE; also termed the electrophile response element). Because of their potent and diverse means to defend against xenobiotic challenge, there has been significant interest in finding effective but non-toxic inducers of phase II defenses as a prophylaxis against chronic diseases (e.g., diabetes, cancer, and neurodegenerative disorders) and pathologies where reactive oxygen and nitrogen species (ROS, RNS, respectively) are associated. The dithiol compound, a-lipoic acid (LA), may be one such phase II inducing compound. This review will focus on the known means of regulating the phase II detoxification response through induction of Nrf2 as well as both the theoretical and known role of LA to stimulate Nrf2-mediated phase II gene induction. In particular, this role will be discussed in the context of LA to upregulate glutathione (GSH) synthesis genes, quintessential phase II enzymes regulated by Nrf2.
