The Keap1-Nrf2 Cellular Defense Pathway: Mechanisms of Regulation and Role in Protection Against Drug-Induced Toxicity

Abstract

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.

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“…Responding to oxidative stress, Nrf2 induces transcription of antioxidant response element-bearing genes, in addition to antioxidant-encoding genes (e.g., GSH-synthesizing enzymes), and phase II detoxifying enzymes and transporters (13,28). Nrf2 induces expression of many cytoprotective proteins responsible for maintaining cellular redox stability.…”

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“…Specifically, nifurtimox and nifurtimox plus TM combination treatment causes up-regulation of several target genes of the Nrf2 pathway, regarded as the most important pathway in protecting cells against oxidative stress (41)(42)(43)(44)(45). Using Ingenuity software to analyze the microarray data in a nonrandom fashion, this pathway was regarded as the most highly involved pathway.…”

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“…Nrf2 is targeted by Keap1 (Kelch-like ECH-associated protein1) for ubiquitylation and proteasomal degradation under normal condition [7]. When faced with cellular stressing signals (e.g., oxidative stress), the interaction between Nrf2 and Keap1 is disrupted, resulting in Nrf2 stabilization and translocation from cytoplasm to the nucleus, which is regarded as canonical way of Nrf2 activation [8]. As a result, the nuclear Nrf2 binds to antioxidant response elements (AREs) or electrophile response elements (EpREs) to deal with the stressing signals [9][10][11].…”