Song Mingchen, Kellum John A, Kaldas Hoda, Fink Mitchell P
Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh Pennsylvania, USA.
J Pharmacol Exp Ther. 2004 Jan;308(1):307-16. doi: 10.1124/jpet.103.056622. Epub 2003 Oct 20.
Ethyl pyruvate (EP), an effective scavenger of reactive oxygen species, is also an anti-inflammatory agent in a variety of in vivo and in vitro model systems. To gain a better understanding of the molecular basis for the anti-inflammatory effects of EP, we compared the pharmacological properties of EP andN-acetyl-l-cysteine (NAC), a well studied scavenger of reactive oxygen species and a precursor for the endogenous antioxidant glutathione (GSH). The studies were performed using RAW 264.7 murine macrophage-like cells that were stimulated with lipopolysaccharide (LPS). Although EP and NAC both inhibited LPS-induced nitric oxide and interleukin (IL)-6 secretion, the former compound was considerably more potent than the latter. EP markedly inhibited inducible nitric-oxide synthase, IL-6, and IL-10 mRNA induction, whereas the effects of NAC were minimal. EP inhibited LPS-induced nuclear factor-kappaB DNA binding to a much greater extent than did NAC. Both compounds inhibited LPS-induced lipid peroxidation, but the two compounds had qualitatively different effects on cellular levels of GSH. Although NAC increased GSH levels, EP had the opposite effect. The anti-inflammatory effects of EP were partially reversed when RAW 264.7 cells were treated with a cell-permeable GSH analog, glutathione ethyl ester. These data support the view that the anti-inflammatory effects of EP are mediated, at least in part, by the ability of EP to deplete cellular GSH stores. Moreover, the findings presented here suggest that an unusual combination of biochemical effects (inhibition of lipid peroxidation and GSH depletion) might account for the anti-inflammatory effects of EP.
丙酮酸乙酯（EP）是一种有效的活性氧清除剂，在多种体内和体外模型系统中也是一种抗炎剂。为了更好地理解EP抗炎作用的分子基础，我们比较了EP与N-乙酰-L-半胱氨酸（NAC）的药理特性，NAC是一种经过充分研究的活性氧清除剂，也是内源性抗氧化剂谷胱甘肽（GSH）的前体。研究使用经脂多糖（LPS）刺激的RAW 264.7小鼠巨噬细胞样细胞进行。尽管EP和NAC都抑制LPS诱导的一氧化氮和白细胞介素（IL）-6分泌，但前一种化合物的效力明显高于后一种。EP显著抑制诱导型一氧化氮合酶、IL-6和IL-10 mRNA的诱导，而NAC的作用微乎其微。EP比NAC更能抑制LPS诱导的核因子-κB与DNA的结合。两种化合物都抑制LPS诱导的脂质过氧化，但它们对细胞内GSH水平的影响在性质上有所不同。尽管NAC增加了GSH水平，但EP却产生相反的效果。当用细胞可渗透的GSH类似物谷胱甘肽乙酯处理RAW 264.7细胞时，EP的抗炎作用部分被逆转。这些数据支持这样一种观点，即EP的抗炎作用至少部分是由EP耗尽细胞内GSH储备的能力介导的。此外，这里呈现的研究结果表明，生化作用的一种不寻常组合（抑制脂质过氧化和GSH耗竭）可能是EP抗炎作用的原因。
