THE PRODUCT OF THE CYP11B2 GENE IS REQUIRED FOR ALDOSTERONE BIOSYNTHESIS IN THE HUMAN ADRENAL-CORTEX
THE PRODUCT OF THE CYP11B2 GENE IS REQUIRED FOR ALDOSTERONE BIOSYNTHESIS IN THE HUMAN ADRENAL-CORTEX
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DOI：
10.1210/mend-5-10-1513
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发表时间：
1991-10-01
影响因子：
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通讯作者：
WHITE, PC
中科院分区：
文献类型：
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作者：
CURNOW, KM;TUSIELUNA, MT;WHITE, PC
类固醇11-β-羟基酶(P450c11)负责在肾上腺皮质束状带将11-脱氧皮质醇转化为皮质醇。动物研究表明，这种酶或密切相关的同工酶也负责球状带合成醛固酮所需的脱氧皮质酮的11-β和18-羟基化和18-氧化。人类有两个不同的11-β-羟基酶基因，分别是CYP11B1和CYP11B2，它们被预测编码的蛋白质有93%的氨基酸同源性。我们用基于聚合酶链式反应的灵敏的方法分析了细胞色素P11B1和B2基因的表达。在正常肾上腺手术标本和分泌醛固酮的肾上腺肿瘤中也检测到高水平的CYP11B1转录本。在正常肾上腺中发现低水平的CYP11B2转录本，而在分泌醛固酮的肿瘤中发现高水平的转录本。生理水平的血管紧张素-II可使培养的肾小球带细胞中的细胞色素P11B2mRNA水平升高。从肿瘤组织中克隆了CYP11B1和B2cDNAs的完整编码区。这些基因在培养的COS-1细胞中的表达表明，CYP11B1产物只能11-β-羟化11-脱氧皮质醇或脱氧皮质酮，而CYP11B2产物也能18-羟化皮质醇或皮质酮。只有在表达细胞色素P11B2基因的细胞中，脱氧皮质酮才能合成少量的醛固酮。这些数据表明，在合成醛固酮的最后几步中，需要使用该产物。
The steroid 11-beta-hydroxylase (P450c11) enzyme is responsible for the conversion of 11-deoxycortisol to cortisol in the zona fasciculata of the adrenal cortex. Animal studies have suggested that this enzyme or a closely related isozyme is also responsible for the successive 11-beta- and 18-hydroxylation and 18-oxidation of deoxycorticosterone required for aldosterone synthesis in the zona glomerulosa. There are two distinct 11-beta-hydroxylase genes in man, CYP11B1 and CYP11B2, which are predicted to encode proteins with 93% amino acid identity. We used a sensitive assay based on the polymerase chain reaction to analyze the expression of the CYP11B1 and B2 genes. Transcripts of CYP11B1 were detected at high levels in surgical specimens of normal adrenals and also in an aldosterone-secreting adrenal tumor. Transcripts of CYP11B2 were found at low levels in normal adrenals, but at a much higher level in the aldosterone-secreting tumor. CYP11B2 mRNA levels were increased in cultured zona glomerulosa cells by physiological levels of angiotensin-II. The entire coding regions of both CYP11B1 and B2 cDNAs were cloned from the tumor mRNA. Expression of these cDNAs in cultured COS-1 cells demonstrated that the CYP11B1 product could only 11-beta-hydroxylate 11-deoxycortisol or deoxycorticosterone, whereas the CYP11B2 product could also 18-hydroxylate cortisol or corticosterone. A small amount of aldosterone was synthesized from deoxycorticosterone only in cells expressing CYP11B2 cDNA. These data demonstrate that the product of CYP11B2 is required for the final steps in the synthesis of aldosterone.