The rise of antioxidant signaling-The evolution and hormetic actions of Nrf2

Journal Article · Thu Apr 01 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.01.011· OSTI ID:21344901

Maher, Jonathan ^[1]; Yamamoto, Masayuki ^[1]

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1. Department of Medicinal Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575 (Japan)

Organisms have evolved sophisticated and redundant mechanisms to manage oxidative and electrophilic challenges that arise from internal metabolism or xenobiotic challenge for survival. NF-E2-related factor 2 (Nrf2) is a transcription factor that has evolved over millennia from primitive origins, with homologues traceable back to invertebrate Caenorhabditis and Drosophila species. The ancestry of Nrf2 clearly has deep-seated roots in hematopoiesis, yet has diversified into a transcription factor that can mediate a multitude of antioxidant signaling and detoxification genes. In higher organisms, a more sophisticated means of tightly regulating Nrf2 activity was introduced via the cysteine-rich kelch-like ECH-associated protein 1 (Keap1), thus suggesting a need to modulate Nrf2 activity. This is evidenced in Keap1{sup -/-} mice, which succumb to juvenile mortality due to hyperkeratosis of the gastrointestinal tract. Although Nrf2 activation protects against acute toxicity and prevents or attenuates several disease states, constitutive activation in some tumors leads to poor clinical outcomes, suggesting Nrf2 has evolved in response to a multitude of selective pressures. The purpose of this review is to examine the origins of Nrf2, while highlighting the versatility and protective abilities elicited upon activation. Various model systems in which Nrf2 is normally beneficial but in which exaggerated pharmacology exacerbates a physiological or pathological condition will be addressed. Although Darwinian principles have selected Nrf2 activity for maximal beneficial effect based on environmental and oxidative challenge, both sub- or super-physiological effects have been noted to be detrimental. The functions of Nrf2 thus suggest a hormetic factor that has evolved empirically over time.

• OSTI ID: 21344901
• Journal Information: Toxicology and Applied Pharmacology, Vol. 244, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.01.011; PII: S0041-008X(10)00022-0; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIOXIDANTS
BLOOD FORMATION
CYSTEINE
DETOXIFICATION
DROSOPHILA
EVOLUTION
GASTROINTESTINAL TRACT
JUVENILES
METABOLISM
MICE
MORTALITY
ONCOGENES
OXIDATION
PHARMACOLOGY
STRESSES
TOXICITY
TRANSCRIPTION FACTORS
AMINO ACIDS
ANIMALS
ARTHROPODS
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
DIGESTIVE SYSTEM
DIPTERA
FLIES
FRUIT FLIES
GENES
INSECTS
INVERTEBRATES
MAMMALS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
PROTEINS
RODENTS
THIOLS
VERTEBRATES