The Nrf2-Keap1 defence pathway: role in protection against drug-induced toxicity.
The metabolic biotransformation of xenobiotics to chemically reactive metabolites can, in some instances, underlie the pathogenesis of certain adverse drug reactions, due to the development of chemical or oxidative stress. In order to guard against such stresses, mammalian cells have evolved multi-faceted, highly-regulated defence systems, one of the most important being that which is regulated by the transcription factor Nrf2. Through regulating the expression of numerous cytoprotective genes, Nrf2 serves as a critical determinant of a cell's capacity to survive, or succumb, to a toxic insult. The aim of this review is to summarise our current understanding of the biochemistry that underlies the Nrf2 defence pathway, and highlight the important role of this transcription factor in the protection against drug-induced toxicity, primarily through the examination of recent investigations that have demonstrated an increased vulnerability to various toxins in animals lacking Nrf2.
Copple
Ian M
IM
The Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, Merseyside L69 3GE, UK.
Goldring
Christopher E
CE
Kitteringham
Neil R
NR
Park
B Kevin
BK
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015262:Xenobiotics / Q000037:antagonists & inhibitors* / Q000633:toxicity
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D015262:Xenobiotics