胆道感染患者肝胆汁中氧甾醇的来源
Origin of oxysterols in hepatic bile of patients with biliary infection.
作者信息
Yoshida Tadashi, Matsuzaki Yasushi, Haigh W Geoffrey, Fukushima Sugano, Ikezawa Kazuto, Tanaka Naomi, Lee Sum P
机构信息
Division of Gastroenterology, Tsukuba Memorial Hospital and Institute of Clinical Medicine, University of Tsukuba, Japan.
出版信息
Am J Gastroenterol. 2003 Oct;98(10):2275-80. doi: 10.1111/j.1572-0241.2003.07703.x.
OBJECTIVES
Oxysterols are ubiquitous in the body and are potential cytotoxic agents in addition to being metabolic regulators. Although bile contains high concentrations of cholesterol, oxysterol concentrations in bile and the effect of infection on oxysterol levels have not been measured, nor has their origin been studied. The purpose of this study was to determine if infection of the biliary tract was associated with increased concentrations of oxysterols in the bile and, if so, which oxysterols showed a significant change.
METHODS
Hepatic bile was obtained from eight patients with biliary tract disease by means of a naso-biliary catheter. Oxysterols were extracted and purified by solid-phase extraction, derivatized and measured by gas chromatography-mass spectrometry.
RESULTS
The following were quantified in hepatic bile: 7-alpha-hydroxycholesterol, 7-beta-hydroxycholesterol, cholestan-3-beta,5-alpha,6-beta-triol, 25-hydroxycholesterol, 26-hydroxycholesterol, 7-ketocholesterol, and 7-alpha-hydroxy-4-cholesten-3-one. Total oxysterols in hepatic bile ranged from 0.133 mumol/L to 7.748 mumol/L (1.47 +/- 2.55 mumol/L). Levels of 7-alpha-hydroxycholesterol and 7-beta-hydroxycholesterol were increased in infected bile (14.2 +/- 15.1 x 10(-3)% of cholesterol vs 1.9 +/- 0.5 x 10(-3)% of cholesterol, p < 0.05, and 22.0 +/- 25.0 x 10(-3)% of cholesterol vs 1.6 +/- 1.2 x 10(-3)% of cholesterol, p < 0.05, respectively). Serum C-reactive protein levels correlated positively with biliary levels of 7-alpha-hydroxycholesterol (R = 0.948), 7-beta-hydroxycholesterol (R = 0.976), cholestan-3-beta,5-alpha,6-beta-triol (R = 0.823), 7-alpha-hydroxy-4-cholesten-3-one (R = 0.846,) and 7-ketocholesterol (R = 0.973). Different oxysterols were found in gallstones, chiefly 3-keto-cholest-4-ene (624 +/- 316 parts per million [ppm] of dry weight), 3-keto-cholesta-4,6-diene (240 +/- 329 ppm) and 7-keto-cholesterol (77 +/- 81 ppm). Incubation of human leukocytes with model bile in the presence of bacterial lipopolysaccharide resulted in changes in sterol composition, including increases in oxysterols. We have identified and quantified oxysterols from uninfected and infected human hepatic bile and from gallstones and gallbladder bile. Biliary infection may be involved in the biogenesis of oxysterols in bile through the production of reactive oxygen species from activated leukocytes.
目的
氧化甾醇在体内广泛存在，除作为代谢调节因子外，还是潜在的细胞毒性剂。尽管胆汁中含有高浓度的胆固醇，但尚未测定胆汁中氧化甾醇的浓度以及感染对氧化甾醇水平的影响，其来源也未得到研究。本研究的目的是确定胆道感染是否与胆汁中氧化甾醇浓度升高有关，如果是，哪些氧化甾醇显示出显著变化。
方法
通过鼻胆管从8例胆道疾病患者获取肝胆汁。氧化甾醇通过固相萃取法提取和纯化，衍生化后用气相色谱 - 质谱法测定。
结果
在肝胆汁中对以下物质进行了定量分析：7-α-羟基胆固醇、7-β-羟基胆固醇、胆甾烷-3-β,5-α,6-β-三醇、25-羟基胆固醇、26-羟基胆固醇、7-酮胆固醇和7-α-羟基-4-胆甾烯-3-酮。肝胆汁中总氧化甾醇浓度范围为0.133μmol/L至7.748μmol/L（1.47±2.55μmol/L）。感染胆汁中7-α-羟基胆固醇和7-β-羟基胆固醇水平升高（分别为胆固醇的14.2±15.1×10⁻³% 与1.9±0.5×10⁻³%，p<0.05；以及胆固醇的22.0±25.0×10⁻³% 与1.6±1.2×10⁻³%，p<0.05）。血清C反应蛋白水平与胆汁中7-α-羟基胆固醇（R = 0.948）、7-β-羟基胆固醇（R = 0.976）、胆甾烷-3-β,5-α,6-β-三醇（R = 0.823）、7-α-羟基-4-胆甾烯-3-酮（R = 0.846）和7-酮胆固醇（R = 0.973）呈正相关。在胆结石中发现了不同的氧化甾醇，主要是3-酮-胆甾-4-烯（干重624±316 ppm）、3-酮-胆甾-4,6-二烯（240±329 ppm）和7-酮胆固醇（77±81 ppm）。在细菌脂多糖存在下，人白细胞与模拟胆汁孵育导致甾醇组成发生变化，包括氧化甾醇增加。我们已鉴定并定量了未感染和感染的人肝胆汁、胆结石和胆囊胆汁中的氧化甾醇。胆道感染可能通过活化白细胞产生活性氧参与胆汁中氧化甾醇的生物合成。
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