Madesh M, Balasubramanian K A
Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College & Hospital, Vellore, India.
Biochem Pharmacol. 1998 May 1;55(9):1489-95. doi: 10.1016/s0006-2952(97)00642-4.
Inflammation is associated with oxidative stress and altered cellular calcium homeostasis. Our earlier studies have shown that, increased phosphatidic acid (PA) formation occurred in enterocyte mitochondria when exposed to superoxide, divalent metal ions or polyamines resulting in altered lipid composition. Since aminosalicylates are the drug of choice for gut inflammation, we have tested the effect of aminosalicylates on PA formation by enterocyte mitochondria. When stimulated by superoxide, Ca2+ or spermine, phosphatidyleth-anolamine (PE) degradation and PA formation occurred in enterocyte mitochondria which can be inhibited by aminosalicylates. The inhibition was 50-60% at 0.5-mM concentration and at 1- or 2-mM final concentration, complete inhibition was observed. Both 5-aminosalicylate (5-ASA) and 4-aminosalicylate (4-ASA) showed similar effects. The stimulation of PA formation by calcium or spermine was not due to increased generation of superoxide by mitochondria which was confirmed by measurement of superoxide production by the mitochondria. These studies suggest that in addition to other cellular effects, aminosalicylates may prevent the enterocyte mitochondrial damage by inhibition of PA formation and PE degradation and alteration of mitochondrial lipid composition.
炎症与氧化应激及细胞钙稳态改变相关。我们早期的研究表明，肠上皮细胞线粒体在暴露于超氧化物、二价金属离子或多胺时，磷脂酸（PA）生成增加，导致脂质组成改变。由于氨基水杨酸盐是治疗肠道炎症的首选药物，我们测试了氨基水杨酸盐对肠上皮细胞线粒体PA生成的影响。当受到超氧化物、Ca2+或精胺刺激时，肠上皮细胞线粒体中会发生磷脂酰乙醇胺（PE）降解和PA生成，而氨基水杨酸盐可抑制这一过程。在0.5 mM浓度时抑制率为50 - 60%，在1 mM或2 mM终浓度时观察到完全抑制。5 - 氨基水杨酸（5 - ASA）和4 - 氨基水杨酸（4 - ASA）表现出相似的效果。钙或精胺对PA生成的刺激并非由于线粒体超氧化物生成增加，这一点通过测量线粒体超氧化物产生得以证实。这些研究表明，除了其他细胞效应外，氨基水杨酸盐可能通过抑制PA生成、PE降解以及改变线粒体脂质组成来预防肠上皮细胞线粒体损伤。
