Rodrigues C M, Kren B T, Steer C J, Setchell K D
Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
J Lipid Res. 1996 Mar;37(3):540-50.
We recently demonstrated that the formation of delta 22-bile acids is a quantitatively major pathway for normal bile acid synthesis in the adult male Sprague-Dawley rat. This pathway is specific for 7 beta-hydroxy bile acids and, when ursodeoxycholic acid is administered, delta 22-ursodeoxycholic acid appears as a major metabolite in the liver tissue, bile, intestinal contents, and plasma. The aims of this study were, therefore, to determine whether this metabolic pathway was gender specific, and to establish that the peroxisome is a site of formation of delta 22-bile acids. Bile acids were determined by gas chromatography-mass spectrometry in liver tissue, jejunum, and plasma of adult female rats and in animals fed a diet containing 0.4% and 1% ursodeoxycholic acid. Bile acid metabolism in female rats was found to be similar to that of male rats, and delta 22-beta-muricholic acid, rather than beta-muricholate, was likewise confirmed as the major muricholic acid synthesized. Ursodeoxycholic acid administration resulted in the appearance of delta 22-ursodeoxycholic acid as a major metabolite. When adult male Sprague-Dawley rats were treated with clofibrate, a drug that induces peroxisomal proliferation, liver weight increased 40-60% and total bile acid synthesis decreased markedly, but the relative composition of individual bile acids was unchanged. When ursodeoxycholic acid was added to the diet, the proportion of delta 22-bile acids relative to the corresponding saturated analogues increased significantly compared with untreated rats, indicating that clofibrate had "amplified" the pathway for formation of delta 22-bile acids. When UDCA was incubated in vitro with a peroxisomal-enriched fraction from normal adult male rat liver, delta 22-ursodeoxycholic acid was formed in proportions comparable to that observed in vivo when this bile acid was given orally. These studies establish that the pathway for the formation of delta 22-bile acids is not gender specific and mainly occurs in hepatic peroxisomes.
我们最近证明，δ22-胆汁酸的形成是成年雄性Sprague-Dawley大鼠正常胆汁酸合成的一个主要定量途径。该途径对7β-羟基胆汁酸具有特异性，当给予熊去氧胆酸时，δ22-熊去氧胆酸会作为主要代谢产物出现在肝组织、胆汁、肠内容物和血浆中。因此，本研究的目的是确定该代谢途径是否具有性别特异性，并确定过氧化物酶体是否是δ22-胆汁酸的形成部位。通过气相色谱-质谱法测定成年雌性大鼠以及喂食含0.4%和1%熊去氧胆酸饲料的动物的肝组织、空肠和血浆中的胆汁酸。发现雌性大鼠的胆汁酸代谢与雄性大鼠相似，同样证实合成的主要鼠胆酸是δ22-β-鼠胆酸，而非β-鼠胆酸盐。给予熊去氧胆酸导致δ22-熊去氧胆酸作为主要代谢产物出现。当成年雄性Sprague-Dawley大鼠用氯贝丁酯（一种诱导过氧化物酶体增殖的药物）处理时，肝脏重量增加40%-60%，总胆汁酸合成显著减少，但单个胆汁酸的相对组成未变。当在饮食中添加熊去氧胆酸时，与未处理的大鼠相比，δ22-胆汁酸相对于相应饱和类似物的比例显著增加，表明氯贝丁酯“放大”了δ22-胆汁酸的形成途径。当熊去氧胆酸在体外与来自正常成年雄性大鼠肝脏的富含过氧化物酶体的部分一起孵育时，形成的δ22-熊去氧胆酸的比例与口服该胆汁酸时在体内观察到的比例相当。这些研究证实，δ22-胆汁酸的形成途径不具有性别特异性，且主要发生在肝脏过氧化物酶体中。
