Department of Clinical Biochemistry, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
J Steroid Biochem Mol Biol. 2013 Nov;138:334-47. doi: 10.1016/j.jsbmb.2013.07.013. Epub 2013 Jul 31.
Deficiency of 21-hydroxylase provides an in vivo model of intrauterine induction of enzymes participating in steroid anabolism and catabolism. Quantitative data for 93 steroid metabolites in urine from 111 patients and 7 controls (25 samples) were compared over the first six weeks of life. Net flux through the key anabolic enzymes was examined by comparison of the totals of steroids derived from the intermediates prior to and following each enzymatic step. Metabolic relationships were established on structural grounds and by Pearson correlation. The relative importance of each catabolic route was evaluated after summing metabolites classified according to their structure as fetal, neonatal, and classical (adult) type. Hierarchical cluster analysis identified the structure at C3-C5 as a key distinguishing feature of the major catabolic streams and demonstrated a split point in metabolic pattern in patients at 7 days. Changes with time in steroid metabolism, larger in patients than in controls, could be interpreted as reflecting increased cortisol demand post partum, the clinical onset of salt-wasting and a transition in catabolism from fetal to postnatal life. Faster involution of the fetal zone and pronounced enhancement of steroid production in zona fasciculata and zona glomerulosa were indicated in patients. Predominant at birth were 'planar' fetal-type 5α-reduced metabolites, adapted to placental excretion, which gave way to additionally hydroxylated neonatal-type metabolites, facilitating renal excretion. Classical metabolism made gains over the study period. Overproduction of steroids in utero in 21-hydroxylase deficiency would have induced fetal catabolic pathways dependent on 5α-reduction. A progressive increase of steroids likely to arise from 5α-reductase type 2 activity, again more distinct in disease, was observed. We demonstrate that the key intermediates in the hypothetical 'backdoor' pathway of androgen synthesis are part of a broader catabolic network and should not be examined in isolation.
21-羟化酶缺乏为参与甾体生物合成和分解代谢的酶在宫内诱导提供了体内模型。比较了 111 例患者和 7 例对照（25 个样本）出生后前 6 周尿液中的 93 种甾体代谢物的定量数据。通过比较每个酶步骤前后从中间产物衍生的类固醇总量，检查关键合成酶的净通量。基于结构和 Pearson 相关建立了代谢关系。根据其结构将代谢物分类为胎儿型、新生儿型和经典（成人）型后，评估了每条分解途径的相对重要性。层次聚类分析确定了 C3-C5 处的结构为主要分解流的关键区别特征，并在第 7 天患者中显示了代谢模式的分岔点。与对照组相比，患者的类固醇代谢变化时间更长，可以解释为产后皮质醇需求增加、盐耗竭的临床发作以及从胎儿到产后生活的分解代谢转变。患者的胎儿区更快地退化，并且在束状带和球状带中类固醇的产生明显增强。出生时主要是适应胎盘排泄的“平面”胎儿型 5α-还原代谢物，随后是另外羟化的新生儿型代谢物，有利于肾脏排泄。经典代谢在研究期间取得进展。21-羟化酶缺乏症患者子宫内类固醇过度产生会诱导依赖于 5α-还原的胎儿分解途径。观察到可能由于 5α-还原酶 2 型活性增加而产生的类固醇过度产生，在疾病中更为明显。我们证明，雄激素合成假设的“后门”途径中的关键中间产物是更广泛的分解代谢网络的一部分，不应该孤立地检查。
