Arsenic is present in the environment and has become a worldwide health concern due to its toxicity and carcinogenicity. However, the specific mechanism(s) by which
arsenic elicits its toxic effects has yet to be fully elucidated. The
transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been recognized as the master regulator of a cellular defense mechanism against toxic insults. This review highlights studies demonstrating that
arsenic activates the Nrf2-Keap1
antioxidant pathway by a distinct mechanism from that of natural compounds such as
sulforaphane (SF) found in broccoli sprouts or tert-butylhyrdoquinone (
tBHQ), a natural
antioxidant commonly used as a food preservative. Evidence also suggests that
arsenic prolongs Nrf2 activation and may mimic constitutive activation of Nrf2, which has been found in several human
cancers due to disruption of the Nrf2-Keap1 axis. The current literature strongly suggests that activation of Nrf2 by
arsenic potentially contributes to, rather than protects against,
arsenic toxicity and carcinogenicity. The mechanism(s) by which known Nrf2 activators, such as the natural chemopreventive compounds SF and
lipoic acid, protect against the deleterious effects caused by
arsenic will also be discussed. These findings will provide insight to further understand how
arsenic promotes a prolonged Nrf2 response, which will lead to the identification of novel molecular markers and development of rational
therapies for the prevention or intervention of
arsenic-induced diseases. The National Institute of Environmental Health Science (NIEHS) Outstanding New Environmental Scientist (ONES) award has provided the opportunity to review the progress both in the fields of
arsenic toxicology and Nrf2 biology. Much of the funding has led to (1) the novel discovery that
arsenic activates the Nrf2 pathway by a mechanism different to that of other Nrf2 activators, such as
sulforaphane and
tert-butylhydroquinone, (2) activation of Nrf2 by chemopreventive compounds protects against
arsenic toxicity and carcinogenicity both in vitro and in vivo, (3) constitutive activation of Nrf2 by disrupting Keap1-mediated negative regulation contributes to
cancer and chemoresistance, (4) p62-mediated sequestration of Keap1 activates the Nrf2 pathway, and (5)
arsenic-mediated Nrf2 activation may be through a p62-dependent mechanism. All of these findings have been published and are discussed in this review. This award has laid the foundation for my laboratory to further investigate the molecular mechanism(s) that regulate the Nrf2 pathway and how it may play an integral role in
arsenic toxicity. Moreover, understanding the biology behind
arsenic toxicity and carcinogenicity will help in the discovery of potential strategies to prevent or control
arsenic-mediated adverse effects.