Nrf2 the rescue: Effects of the antioxidative/electrophilic response on the liver
Section snippets
Historical perspective
The first suggestion of the transcriptional regulation of cytoprotective enzymes was described with the idea of monofunctional and bifunctional inducers (Talalay, 1989). Compounds, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polycyclic aromatics, and β-naphthoflavone, are considered bifunctional inducers, in that they increase both phase-I [ i.e. cytochrome p450 s (Cyps), NAD(P)H quinone oxidoreductase 1 (Nqo1)] and phase-II [i.e. glutathione-S-transferases (Gsts) and
Higher susceptibility of Nrf2-null mice to hepatic injury
The potential for Nrf2 to induce many cytoprotective genes, in response to certain stimuli, permits Nrf2 to be extremely diverse in facilitating hepatoprotection from a variety of chemical-and oxidative stress-induced pathologies. Experiments have shown that targeted deletion of Nrf2, as in Nrf2-null mice, leads to enhanced susceptibility to hepatic injury. The first compound selected to illustrate the effects of a loss of Nrf2 was acetaminophen, a well-known and often used hepatotoxicant.
Distribution
Many drugs and other xenobiotics are concentrated in the liver due to their uptake by transporters. Uptake transporters expressed in the liver include the bile acid transporter Na+-taurocholate cotransporting polypeptide (Ntcp), organic anion-transporting polypeptide 1a1 (Oatp1a1), Oatp1a4, Oatp1b2, organic cation transporter 1 (Oct1), organic anion transporter 2 (Oat2), equilibrative nucleoside transporter 1 (Ent1) and Atp8b1 (Klaassen and Lu, 2008). In general, Nrf2 does not affect the mRNA
Concluding remarks
Nrf2 has emerged as a transcription factor that is capable of inducing a wide battery of genes that aid in the detoxification and elimination of xenobiotics. Evolutionarily speaking, such a transcription factor as Nrf2 is extremely advantageous in an environment where organisms are constantly bombarded with electrophilic and oxidative stress. In regard to pharmacology and toxicology, Nrf2 has evolved to be an important transcription factor. For pharmacology, Nrf2 must be considered because of
Acknowledgments
The authors would like to thank the members of the Klaassen laboratory for manuscript revision assistance. The writing of this review article was financially supported by NIH Grant DK081461.
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