Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis

• Published in: Biochimica et biophysica acta Vol. 1840; no. 1; pp. 209 - 218
• Main Authors: Zhou, Richard, Lin, Jianjun, Wu, Defeng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2014
• Subjects: Animals; Anti-Infective Agents, Local - toxicity; Anticarcinogenic Agents - pharmacology; Autophagy; Binge alcohol; Blotting, Western; CYP2E1:cytochrome p4502E1; Cytochrome P-450 CYP2E1 - physiology; Ethanol - toxicity; Fatty Liver - chemically induced; Fatty Liver - metabolism; Fatty Liver - prevention & control; Glutathione - metabolism; Heme Oxygenase-1 - metabolism; Hep G2 Cells; Humans; Isothiocyanates - pharmacology; Lipid Peroxidation - drug effects; Liver - drug effects; Liver - metabolism; Liver steatosis; Male; Mice; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative Stress - drug effects; Sulforaphane; Sulfoxides; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Binge alcohol; CYP2E1:cytochrome p4502E1; Nrf2; Sulforaphane; Liver steatosis
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.09.018

The mechanism(s) by which alcohol causes cell injury are still not clear but a major mechanism appears to be the role of lipid peroxidation and oxidative stress in alcohol toxicity. CYP2E1-generated ROS contributes to the ethanol-induced oxidant stress and inhibition of CYP2E1 activity decreases ethanol-induced fatty liver. The transcription factor Nrf2 regulates the expression of many cytoprotective enzymes which results in cellular protection against a variety of toxins. The current study was designed to evaluate the ability of sulforaphane, an activator of Nrf2, to blunt CYP2E1-dependent, ethanol-induced steatosis in vivo and in vitro. The sulforaphane treatment activated Nrf2, increased levels of the Nrf2 target heme oxygenase-1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-nitrotyrosine protein adducts and an increase in GSH levels after the acute ethanol treatment. It decreased ethanol-elevated liver levels of triglycerides and cholesterol and Oil Red O staining. Similar results were found in vitro as addition of sulforaphane to HepG2 E47 cells, which express CYP2E1, elevated Nrf2 levels and decreased the accumulation of lipid in cells cultured with ethanol. Sulforaphane treatment had no effect on levels of or activity of CYP2E1. Sulforaphane proved to be an effective in vivo inhibitor of acute ethanol-induced fatty liver in mice. The possible amelioration of liver injury which occurs under these conditions by chemical activators of Nrf2 is of clinical relevance and worthy of further study. •Activation of Nrf2 by sulforaphane was studied in CYP2E1 KI mice and HepG2 E47 cells which express CYP2E1.•The activation of Nrf2 by sulforaphane prevents binge-ethanol induced oxidative stress and steatosis in CYP2E1 KI mice.•Sulforaphane prevents ethanol-induced increases in lipid accumulation in HepG2 E47 cells.•Binge-ethanol plus sulforaphane increases hepatic autophagy.•Sulforaphane may be effective in lowering ethanol/CYP2E1-induced liver injury.