Gollan J, Hammaker L, Licko V, Schmid R
J Clin Invest. 1981 Apr;67(4):1003-15. doi: 10.1172/jci110111.
Most previous compartmental models describing bilirubin transport and metabolism in the liver have been validated solely by analysis of the plasma disappearance of radiolabeled bilirubin in human subjects. We now have determined the transport kinetics of a bilirubin tracer pulse by analysis of plasma, liver, and bile radioactivity data from 30 intact rats. Plasma [3H]bilirubin disappearance was best described by the sum of three exponentials, and a six-compartment model, derived by simulation analysis, was necessary and adequate to describe all experimental data. Examination of the injected radiolabeled bilirubin by extraction with hexadecyltrimethylammonium bromide and thin-layer chromatography revealed that 6.6% (mean) of the original pigment had been degraded to labeled nonbilirubin derivatives during preparation of the tracer dose. This material exhibited a significantly longer half-life (mean 50.6 min) of the plasma terminal exponential than that of authentic radiobilirubin (20.6 min). In isolated perfused rat liver, the kinetics of [3H]bilirubin in perfusate and bile readily fitted the proposed model. Compatibility of the model with the data obtained, both in the isolated liver and in vivo, required that a fraction of bilirubin conjugated in the liver be deconjugated and returned to the plasma. Deconjugation of bilirubin glucuronides was evaluated directly by infusion of bilirubin monoglucuronides, containing 14C in the glucuronosyl group, into rats with an external bile fistula. Since metabolic degradation of hydrolyzed 14C-labeled glucuronic acid yields 14CO2, this was measured in expired air. Whereas 86% of the administered labeled pigment was recovered in bile, 7% of the label appeared in 14CO2. These findings directly validate a portion of the proposed kinetic model and suggest that hepatic deconjugation of a small fraction of bilirubin glucuronides is a physiological event. Deconjugation may also account, at least in part, for the presence of increased concentrations of unconjugated bilirubin in the plasma of patients with cholestasis.
以往大多数描述肝脏中胆红素转运和代谢的房室模型仅通过分析人体受试者中放射性标记胆红素的血浆消失情况进行验证。我们现在通过分析来自30只完整大鼠的血浆、肝脏和胆汁放射性数据，确定了胆红素示踪剂脉冲的转运动力学。血浆[3H]胆红素的消失情况最好用三个指数之和来描述，通过模拟分析得出的六房室模型对于描述所有实验数据是必要且充分的。用十六烷基三甲基溴化铵萃取并通过薄层色谱法检查注入的放射性标记胆红素，结果显示在示踪剂剂量制备过程中，6.6%（平均值）的原始色素已降解为标记的非胆红素衍生物。这种物质的血浆终末指数半衰期（平均50.6分钟）明显长于真实放射性胆红素的半衰期（20.6分钟）。在离体灌注大鼠肝脏中，灌注液和胆汁中[3H]胆红素的动力学很容易符合所提出的模型。该模型与在离体肝脏和体内获得的数据的兼容性要求肝脏中结合的一部分胆红素去结合并返回血浆。通过向具有外部胆瘘的大鼠输注葡糖醛酸基团中含有14C的胆红素单葡糖醛酸酯，直接评估了胆红素葡糖醛酸酯的去结合情况。由于水解的14C标记葡糖醛酸的代谢降解产生14CO2，因此在呼出气体中进行了测量。虽然86%的给予的标记色素在胆汁中回收，但7%的标记出现在14CO2中。这些发现直接验证了所提出的动力学模型的一部分，并表明一小部分胆红素葡糖醛酸酯的肝脏去结合是一种生理事件。去结合至少部分也可能解释了胆汁淤积患者血浆中未结合胆红素浓度升高的原因。
