Zhou Richard, Lin Jianjun, Wu Defeng
Depetment of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Biochim Biophys Acta. 2014 Jan;1840(1):209-18. doi: 10.1016/j.bbagen.2013.09.018. Epub 2013 Sep 21.
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.
酒精导致细胞损伤的机制尚不清楚，但主要机制似乎是脂质过氧化和氧化应激在酒精毒性中的作用。细胞色素P450 2E1（CYP2E1）产生的活性氧（ROS）导致乙醇诱导的氧化应激，抑制CYP2E1活性可减轻乙醇诱导的脂肪肝。转录因子核因子E2相关因子2（Nrf2）调节许多细胞保护酶的表达，从而使细胞免受多种毒素的侵害。
本研究旨在评估Nrf2激活剂萝卜硫素在体内和体外减弱CYP2E1依赖性乙醇诱导的脂肪变性的能力。
萝卜硫素处理激活了Nrf2，增加了Nrf2靶标血红素加氧酶-1的水平，随后降低了氧化应激，急性乙醇处理后脂质过氧化和3-硝基酪氨酸蛋白加合物减少以及谷胱甘肽（GSH）水平增加表明了这一点。它降低了乙醇升高的肝脏甘油三酯和胆固醇水平以及油红O染色。在体外也发现了类似的结果，因为向表达CYP2E1的HepG2 E47细胞中添加萝卜硫素可提高Nrf2水平，并减少用乙醇培养的细胞中的脂质积累。萝卜硫素处理对CYP2E1的水平或活性没有影响。
萝卜硫素被证明是小鼠急性乙醇诱导的脂肪肝的有效体内抑制剂。
Nrf2的化学激活剂在这些条件下可能改善肝损伤，这具有临床相关性，值得进一步研究。
