Liu, J; Wu, KC; Lu, YF; Ekuase, E; Klaassen, CD
To investigate the role of Nrf2 as a master defense against the hepatotoxicity produced by various chemicals, Nrf2-null, wild-type, Keap1-knock down (Keap1-Kd) and Keap1-hepatocyte knockout (Keap1-HKO) mice were used as a "graded Nrf2 activation" model. Mice were treated with 14 hepatotoxicants at appropriate doses, and blood and liver samples were collected thereafter (6 h to 7 days depending on the hepatotoxicant). Graded activation of Nrf2 offered a Nrf2-dependent protection against the hepatotoxicity produced by carbon tetrachloride, acetaminophen, microcystin, phalloidin, furosemide, cadmium, and lithocholic acid, as evidenced by serum alanine aminotransferase (ALT) activities and by histopathology. Nrf2 activation also offered moderate protection against liver injury produced by ethanol, arsenic, bromobenzene, and allyl alcohol but had no effects on the hepatotoxicity produced by D-galactosamine/endotoxin and the Fas ligand antibody Jo-2. Graded Nrf2 activation reduced the expression of inflammatory genes (MIP-2, mKC, IL-1 β , IL-6, and TNF α ), oxidative stress genes (Ho-1, Egr1), ER stress genes (Gadd45 and Gadd153), and genes encoding cell death (Noxa, Bax, Bad, and caspase3). Thus, this study demonstrates that Nrf2 prevents the liver from many, but not all, hepatotoxicants. The Nrf2-mediated protection is accompanied by induction of antioxidant genes, suppression of inflammatory responses, and attenuation of oxidative stress.
Alanine aminotransferase; Allyl alcohols; D-galactosamine; Genes encoding; Hepatotoxicity; Inflammatory genes; Inflammatory response; Lithocholic acids; Amino acids; Cell death; Mammals; Gene expression; alanine aminotransferase; alcohol; allyl alcohol; arsenic; bromobenzene; cadmium; carbon tetrachloride; caspase 3; early growth response factor 1; furosemide; growth arrest and DNA damage inducible protein 153; growth arrest and DNA damage inducible protein 45; interleukin 1beta; interleukin 6; lithocholic acid; macrophage inflammatory protein 2; microcystin; paracetamol; phalloidin; protein BAD; protein Bax; transcription factor Nrf2; tumor necrosis factor alpha; Nfe2l2 protein, mouse; transcription factor Nrf2; alanine aminotransferase blood level; animal experiment; animal model; animal tissue; article; cell death; controlled study; endoplasmic reticulum stress; enzyme activity; histopathology; inflammation; liver injury; liver protection; liver toxicity; mouse; nonhuman; oxidative stress; protein expression; wild type; animal; C57BL mouse; disease model; DNA damage; gene expression regulation; genetics; knockout mouse; liver; metabolism; pathology; physiological stress; toxic hepatitis; Mus; Animals; Cell Death; Disease Models, Animal; DNA Damage; Drug-Induced Liver Injury; Endoplasmic Reticulum Stress; Gene Expression Regulation; Inflammation; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Stress, Physiological
