Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Mar;43(3):337-349.
doi: 10.1007/s12272-019-01192-3. Epub 2019 Nov 28.

Nrf2 in liver toxicology

Keiko Taguchi  1 , Thomas W Kensler  2
Affiliations
Review

Nrf2 in liver toxicology

Keiko Taguchi et al. Arch Pharm Res. 2020 Mar.

Abstract

Liver plays essential roles in the metabolism of many endogenous chemicals and exogenous toxicants. Mechanistic studies in liver have been at the forefront of efforts to probe the roles of bioactivation and detoxication of environmental toxins and toxicants in hepatotoxicity. Moreover, idiosyncratic hepatoxicity remains a key barrier in the clinical development of drugs. The now vast Nrf2 field emerged in part from biochemical and molecular studies on chemical inducers of hepatic detoxication enzymes and subsequent characterization of the modulation of drug/toxicant induced hepatotoxicities in mice through disruption of either Nrf2 or Keap1 genes. In general, loss of Nrf2 increases the sensitivity to such toxic chemicals, highlighting a central role of this transcription factor and its downstream target genes as a modifier to chemical stress. In this review, we summarize the impact of Nrf2 on the toxicology of multiple hepatotoxicants, and discuss efforts to utilize the Nrf2 response in predictive toxicology.

Keywords: Hepatocarcinogenesis; Hepatoxicity; Keap1; Nrf2; Xenobiotic metabolism.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest: The authors declare that they have no conflict of interest.

Figures

Figure 1:
Figure 1:. Hepatic shunt in Nrf2 KO mice.
Altered acetaminophen toxicity and portal vasculature in wild-type versus Nrf2 KO C57BL/6J mice. Top. Plasma alanine aminotransferase (ALT) levels in 10-week old fasted wild-type and Nrf2 KO mice following acetaminophen challenge (250 mg/kg, i.p) after 6 hours. Means ± SE. Bottom. Micro computed tomography of livers perfused through the portal vein with radio-opaque Microfil in Nrf2 KO mice with intrahepatic shunt and wild-type mice. Figure adapted from Skoko et al. (2014).
Figure 2:
Figure 2:. Protective roles of Nrf2 in chronic liver diseases.
Sequential alterations of steatosis with lipid accumulation, steatohepatitis with inflammation, cirrhosis with fibrosis and liver cancer can be attenuated by Nrf2 activation.
Figure 3:
Figure 3:. Induction of Nrf2-regulated quinone reductase (NQO1) activity in Hepa1c1c7 mouse hepatoma cells.
There is a vast range in potency (>20,000-fold) of inducers of Nrf2 signaling used in cytoprotection studies. Optimal balance of potency, efficacy and specificity have not been defined in pre-clinical or clinical studies. Values in parentheses are the concentrations required to double NQO1 activity in Hepa1c1c7 cells. BHT, butylated hydroxytoluene; oltipraz, 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione; sulforaphane, (−)-1-isothiocyanato-(4R)-(methylsulfinyl)butane; CDDO-Im, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. Figure adapted from Kensler et al. (2010).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alam J, Shibahara S, Smith A (1989) Transcriptional activation of the heme oxygenase gene by heme and cadmium in mouse hepatoma cells. J Biol Chem 264:6371–6375. - PubMed
    1. Ansher SS, Dolan P, Bueding E (1983) Chemoprotective effects of two dithiolthiones and of butylhydroxyanisole against carbon tetrachloride and acetaminophen toxicity. Hepatology 3:932–935. - PubMed
    1. Anstee QM, Goldin RD (2006) Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 87:1–16. - PMC - PubMed
    1. Benson AM, Batzinger RP, Ou SY, Bueding E, Cha YN, Talalay P (1978) Elevation of hepatic glutathione S-transferase activities and protection against mutagenic metabolites of benzo(a)pyrene by dietary antioxidants. Cancer Res 38:4486–4495. - PubMed
    1. Benson AM, Hunkeler MJ, Talalay P (1980) Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. Proc Natl Acad Sci U S A 77:5216–5220. - PMC - PubMed

MeSH terms

Substances

-