CEREBROTENDINOUS XANTHOMATOSIS - A DEFECT IN MITOCHONDRIAL 26-HYDROXYLATION REQUIRED FOR NORMAL BIOSYNTHESIS OF CHOLIC-ACID
CEREBROTENDINOUS XANTHOMATOSIS - A DEFECT IN MITOCHONDRIAL 26-HYDROXYLATION REQUIRED FOR NORMAL BIOSYNTHESIS OF CHOLIC-ACID
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DOI：
10.1172/jci109806
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发表时间：
1980-01-01
影响因子：
15.9
通讯作者：
PEDERSEN, JI
中科院分区：
文献类型：
--
作者：
OFTEBRO, H;BJORKHEM, I;PEDERSEN, JI
应用肝组织匀浆不同亚细胞组分和同位素稀释-质谱法，对脑腱黄瘤病患者和正常对照组5.beta.-cholestane-3.alpha.，7.alpha.，12.alpha.-triol侧链氧化进行了研究。在对照组中，5.beta.-cholestane-3.alpha.，7.alpha.，12.alpha.-triol通过线粒体部分转化为5.beta.-cholestane-3.alpha.，7.alpha.，12.alpha.，26-tetrol和3.alpha.，7.alpha.，12.alpha.-trihydroxy-5.beta.-cholestanoic酸，通过微体部分转化为5.beta.-cholestane-3.alpha.，7.alpha.，12.alpha.-25-tetrol。在CTX患者中，肝脏线粒体完全缺乏26-羟基酶活性。相同的线粒体组分催化维生素D3的25-羟基化。服用环磷酰胺的受试者肝脏微粒体部分的5.beta.-cholestane-3.alpha.，7.alpha.，12.alpha.-triol.含量是正常值的50倍以上CTX的基本代谢缺陷似乎是线粒体26-羟基酶的缺乏。在环磷酰胺患者胆汁中观察到的5.beta.-cholestane-3.alpha.，7.alpha.，12.alpha.，25-tetrol和5.beta.-cholestane-3.alpha.，7.alpha.，12.alpha.，24.alpha.，25-pentol的排泄可能是由于26-羟基酶的主要底物5.beta.-cholestane-3.alpha.，7.alpha.，12.alpha.-triol，的积累以及该底物暴露于通常活性较低的微粒体25-和24-羟基酶所致。人体肝脏胆酸生物合成的主要途径可能涉及线粒体C27-类固醇26-羟基化。
Oxidation of the side chain of 5.beta.-cholestane-3.alpha.,7.alpha.,12.alpha.-triol was studied in a patient with cerebrotendinous xanthomatosis (CTX) and in control subjects, using various subcellular fractions of liver homogenate and a method based on isotope dilution-mass spectrometry. In the control, 5.beta.-cholestane-3.alpha.,7.alpha.,12.alpha.-triol was converted into 5.beta.-cholestane-3.alpha.,7.alpha.,12.alpha.,26-tetrol and 3.alpha.,7.alpha.,12.alpha.-trihydroxy-5.beta.-cholestanoic acid by the mitochondrial fraction, and into 5.beta.-cholestane-3.alpha.,7.alpha.,12.alpha.-25-tetrol by the microsomal fraction. In the CTX patient, liver mitochondria were completely devoid of 26-hydroxylase activity. The same mitochondrial fraction catalyzed 25-hydroxylation of vitamin D3. The microsomal fraction of liver of the subject with CTX contained more than 50-fold the normal amount of 5.beta.-cholestane-3.alpha.,7.alpha.,12.alpha.-triol. The basic metabolic defect in CTX appears to be a lack of the mitochondrial 26-hydroxylase. The excretion in the bile of 5.beta.-cholestane-3.alpha.,7.alpha.,12.alpha.,25-tetrol and 5.beta.-cholestane-3.alpha.,7.alpha.,12.alpha.,24.alpha.,25-pentol observed in CTX patients may be secondary to the accumulation of the major substrate for the 26-hydroxylase, i.e., 5.beta.-cholestane-3.alpha.,7.alpha.,12.alpha.-triol, and exposure of this substrate to the normally less active microsomal 25-and 24-hydroxylases. The major pathways in the biosynthesis of cholic acid in human liver may involve a mitochondrial C27-steroid 26-hydroxylation.