The keap1-nrf2 cellular defense pathway: mechanisms of regulation and role in protection against drug-induced toxicity.
Adverse drug reactions pose a significant public health problem. In some cases, the process of drug metabolism can contribute to the onset of toxicity through the bioactivation of a parent molecule to a chemically reactive intermediate. In order to maintain a favorable balance between bioactivation and detoxification, mammalian cells have evolved an inducible cell defense system known as the antioxidant response pathway. The activity of this cytoprotective pathway is largely regulated by the transcription factor Nrf2, which governs the expression of many phase II detoxification and antioxidant enzymes. In turn, the activity of Nrf2 is regulated by the cysteine-rich cytosolic inhibitor Keap1, which acts as a "sensor" for chemical/oxidative stress. This article summarizes our current understanding of the molecular mechanisms that regulate the function of the Keap1-Nrf2 pathway and highlights the importance of Nrf2 in the protection against drug-induced toxicity.
Copple
Ian M
IM
MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, The University of Liverpool, Sherrington Building, Ashton Street, Liverpool, Merseyside L69 3GE, UK.
Goldring
Christopher E
CE
Kitteringham
Neil R
NR
Park
B Kevin
BK
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001711:Biotransformation; D019610:Cytoprotection; D004342:Drug Hypersensitivity / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D054875:Ubiquitination
D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2