Ko W H, Tam S C
Department of Physiology, Chinese University of Hong Kong.
Ren Fail. 1994;16(3):359-66. doi: 10.3109/08860229409044876.
Trichosanthin (TCS) is a ribosome-inactivating protein that has a wide range of biological and pharmacological activities. Due to its small molecular size, TCS is filtered by the glomerulus and can be recovered from urine. A previous experiment showed that the kidney is an important organ for its elimination. However, urine TCS recovery was unexpectedly small, suggesting renal reabsorption of this compound. To substantiate renal TCS reabsorption, different doses of TCS were injected intravenously into rats. Increasing the dose from 0.375 mg/kg to 12 mg/kg enhanced the percentage urine recovery from less than 0.29 +/- 0.06% to 39.07 +/- 2.46%. This demonstrated that TCS is reabsorbed by a saturable mechanism. Reabsorption of most small molecular weight filterable proteins shares a common endocytotic process. It is very likely that TCS utilizes the same process for reabsorption. When a filterable protein such as hemoglobin was infused with TCS, it competed with TCS for reabsorption and therefore increased the percentage urine TCS recovery to 35 +/- 2%. Infusion of another filterable protein, lysozyme, increased recovery to 3.2 +/- 0.8%. This supports the proposal that renal TCS uptake utilizes the common endocytotic mechanism. It was also found in this study that injection of TCS depressed the glomerular filtration rate (GFR), implying renal toxicity. This effect can be attributed to ribosome inactivation which takes place inside the cells. Should reabsorption of TCS be reduced, renal toxicity will disappear. For this purpose, dextran-trichosanthin (DXTCS) conjugate was synthesized to increase its effective molecular size.(ABSTRACT TRUNCATED AT 250 WORDS)
天花粉蛋白（TCS）是一种核糖体失活蛋白，具有广泛的生物学和药理活性。由于其分子尺寸小，TCS可被肾小球滤过，并可从尿液中回收。先前的实验表明，肾脏是其排泄的重要器官。然而，尿液中TCS的回收率出乎意料地低，提示该化合物存在肾重吸收。为证实TCS的肾重吸收，将不同剂量的TCS静脉注射到大鼠体内。剂量从0.375mg/kg增加到12mg/kg，尿液回收率从低于0.29±0.06%提高到39.07±2.46%。这表明TCS通过可饱和机制进行重吸收。大多数可滤过的小分子蛋白质的重吸收具有共同的内吞过程。TCS很可能利用相同的过程进行重吸收。当注入可滤过蛋白如血红蛋白时，它与TCS竞争重吸收，从而使尿液中TCS的回收率提高到35±2%。注入另一种可滤过蛋白溶菌酶，回收率提高到3.2±0.8%。这支持了肾摄取TCS利用共同内吞机制的观点。该研究还发现，注射TCS会降低肾小球滤过率（GFR），提示存在肾毒性。这种效应可归因于细胞内发生的核糖体失活。如果TCS的重吸收减少，肾毒性将消失。为此，合成了葡聚糖-天花粉蛋白（DXTCS）缀合物以增加其有效分子尺寸。（摘要截短于250字）
