Renal reabsorption of trichosanthin and the effect on GFR

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)