TOXICITY OF OXYSTEROLS TO HUMAN MONOCYTE-MACROPHAGES
TOXICITY OF OXYSTEROLS TO HUMAN MONOCYTE-MACROPHAGES
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DOI：
10.1016/0021-9150(95)05594-m
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发表时间：
1995-11-01
期刊：
影响因子：
5.3
通讯作者：
MITCHINSON, MJ
中科院分区：
文献类型：
--
作者：
CLARE, K;HARDWICK, SJ;MITCHINSON, MJ
我们在体外研究了胆固醇氧化产物（氧甾醇）、7 α -羟基胆固醇、7 β -羟基胆固醇、7-酮胆固醇、25-羟基胆固醇和26-羟基胆固醇对人单核巨噬细胞的毒性。7位衍生物存在于硫酸铜（II）氧化的低密度脂蛋白（LDL）和巨噬细胞中，也存在于人类动脉粥样硬化病变的提取物中，这些提取物也含有26-羟基胆固醇。我们还评估了25-羟基胆固醇的毒性，因为它经常被用于3-羟基-3-甲基戊二酰辅酶a （HMG-CoA）还原酶抑制和LDL受体下调的研究。对预负荷氚化腺嘌呤的单核巨噬细胞放射性释放的测量，作为评估细胞毒性的一种手段，表明所有的氧甾醇都表现出时间和浓度依赖性的毒性：26-羟基胆固醇的细胞毒性最强。7位衍生物也产生明显的细胞损伤，尽管浓度高于26-羟基胆固醇。在评估的氧化甾醇中，25-羟基胆固醇的毒性最小。用3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四氮唑（MTT）染料还原试验也证实了7 - β -羟胆固醇和7 - β -羟胆固醇的细胞毒性，证实26-羟胆固醇比7 - β -羟胆固醇毒性更大。单核巨噬细胞与添加不同氧甾醇的胆固醇孵育得到不同的结果。本身无毒性的胆固醇抑制了25-羟基胆固醇和26-羟基胆固醇的毒性，但7位衍生物的毒性不受影响。讨论了这些分子与动脉粥样硬化中巨噬细胞死亡的可能相关性。
We have investigated the toxicity of the cholesterol oxidation products (oxysterols), 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, 7-ketocholesterol, 25-hydroxycholesterol and 26-hydroxycholesterol to human monocyte-macrophages in vitro. The 7-position derivatives are present in low density lipoprotein (LDL) oxidised with copper (II) sulphate and by macrophages, and in extracts of human atherosclerotic lesions, which also contain 26-hydroxycholesterol. We have also assessed 25-hydroxycholesterol for toxicity because it has often been used in studies of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibition and LDL receptor down-regulation. Measurement of radioactivity release from monocyte-macrophages preloaded with tritiated adenine, as a means of assessing cytotoxicity, indicated that all the oxysterols showed time- and concentration-dependent toxicity: The cytotoxic potency of 26-hydroxycholesterol was the greatest. The 7-position derivatives also produced marked cell damage, though at higher concentrations than for 26-hydroxycholesterol. Of the oxysterols assessed, the toxicity of 25-hydroxycholesterol was the least. The cytotoxicity of 7 beta-hydroxycholesterol and 26-hydroxycholesterol was also shown using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) dye reduction assay which confirmed that 26-hydroxycholesterol was more toxic than 7 beta-hydroxycholesterol. Incubation of monocyte-macrophages with cholesterol added to the different oxysterols gave varying results. Cholesterol, which was not itself toxic, inhibited the toxicity of 25-hydroxycholesterol and 26-hydroxycholesterol, but the toxicity of the 7-position derivatives was not affected. The possible relevance of these molecules to the death of macrophages seen in atherosclerosis is discussed.