Tait J F, Tait S A
Moorlands, Brockenhurst, Hampshire.
J Endocrinol. 1991 Dec;131(3):339-57. doi: 10.1677/joe.0.1310339.
Earlier views indicated that globulin (corticosteroid-binding globulin (CBG) or sex hormone-binding globulin (SBG)) but not albumin binding in plasma, protects steroids from splanchnic metabolism in man. Also, the splanchnic extraction (HE) of a steroid seemed to be highly dependent on the rate of disassociation of the steroid-protein complex. However, the faster rate of disassociation (tau 1/2 = 0.9 s) of cortisol-CBG, as determined by later accurate fluorescence methods, intuitively meant that this complex must disassociate completely in a single 9 s passage through the liver. The low HE of total cortisol was then a puzzling anomaly. Using a differential equation solver (TUTSIM) and a model with unbound, albumin- and globulin-bound pools of steroid (with metabolism of unbound and also possibly albumin-bound steroid), the mechanism of splanchnic metabolism has been studied. The 'complex', probably most realistic, model includes 13 steroids, which can simultaneously bind to plasma albumin, CBG and SBG. The steroid concentration and numbers of occupied binding sites of the globulins decrease during the time of metabolism. The experimental data used are the in-vitro binding characteristics of the steroid-protein complexes, including the equilibrium constants and rates of disassociation and the in-vivo HE of nine steroids, usually measured by direct analysis of hepatic venous blood. However, the HE of cortisol had to be calculated from the metabolic clearance rate/splanchnic blood flow, giving a maximum value of 12%. The fractional metabolic rate of unbound steroid is generally represented by e. A certain value of e (RE) is required to give a remaining steroid concentration after 9 s of metabolism, which is made equal to (1-HE) in the model to simulate splanchnic extraction. If the fractional rate of metabolism of albumin-bound steroid is h (f = h/e), then RE will depend on the value of f. The maximum RE for cortisol is RE0 = 0.42 and RE1 = 0.16 for f = 0 and 1 respectively. For either value of RE, there will be the appreciable reassociation of cortisol to CBG after disassociation of the cortisol-CBG complex. With such reassociation, the total cortisol remaining after 9 s metabolism is fairly independent of the rate of dissociation of the cortisol-CBG complex. This explains the low total HE of cortisol in spite of the high rate of disassociation of cortisol-CBG.(ABSTRACT TRUNCATED AT 400 WORDS)
早期观点认为，血浆中球蛋白（皮质类固醇结合球蛋白（CBG）或性激素结合球蛋白（SBG））而非白蛋白的结合，可保护类固醇免受人体内脏代谢的影响。此外，类固醇的内脏提取率（HE）似乎高度依赖于类固醇 - 蛋白质复合物的解离速率。然而，通过后来精确的荧光方法测定，皮质醇 - CBG的解离速率更快（半衰期τ1/2 = 0.9秒），直观地意味着这种复合物在单次通过肝脏的9秒过程中必须完全解离。那么总皮质醇的低HE就是一个令人困惑的异常现象。使用微分方程求解器（TUTSIM）以及一个包含类固醇的未结合、白蛋白结合和球蛋白结合池（包括未结合以及可能白蛋白结合的类固醇的代谢）的模型，对内脏代谢机制进行了研究。这个“复杂”且可能最符合实际的模型包含13种类固醇，它们可同时与血浆白蛋白、CBG和SBG结合。在代谢过程中，类固醇浓度以及球蛋白上被占据的结合位点数量会降低。所使用的实验数据是类固醇 - 蛋白质复合物的体外结合特性，包括平衡常数、解离速率以及9种类固醇的体内HE，通常通过对肝静脉血的直接分析来测量。然而，皮质醇的HE必须根据代谢清除率/内脏血流量来计算，得出的最大值为12%。未结合类固醇的分数代谢率通常用e表示。为了在代谢9秒后得到一个剩余类固醇浓度，需要一个特定的e值（RE），在模型中使其等于（1 - HE）以模拟内脏提取。如果白蛋白结合类固醇的分数代谢率为h（f = h/e），那么RE将取决于f的值。皮质醇的最大RE，f = 0时RE0 = 0.42，f = 1时RE1 = 0.16。对于任何一个RE值，皮质醇 - CBG复合物解离后，皮质醇与CBG都会有明显的重新结合。有了这种重新结合，9秒代谢后剩余的总皮质醇相当独立于皮质醇 - CBG复合物的解离速率。这就解释了尽管皮质醇 - CBG解离速率很高，但总皮质醇的HE却很低的现象。（摘要截断于400字）
