Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.

摘要: Glycoprotein 330 (gp330) is an endocytic receptor expressed in the renal proximal tubules and some other absorptive epithelia, e.g., inner ear. The present study shows that antifibrinolytic polypeptide, aprotinin, nephro- ototoxic antibiotics, aminoglycosides, polymyxin B compete for binding of 125I-urokinase-plasminogen activator inhibitor type-1 complexes to purified rabbit gp330. Half maximal inhibition was measured at 4 microM 50 gentamicin, 0.5 B. Drug gp330 validated by equilibrium dialysis [3H] gentamicin-gp330 incubations binding/uptake studies rat gp330-expressing L2 carcinoma cells. Analyses mutant aprotinins Saccharomyces cerevisiae revealed basic residues are essential uptake. polybasic drugs also antagonized ligand human alpha 2-macroglobulin receptor. However, rapid glomerular filtration suggests kidney be quantitatively most important target. In conclusion, a novel role as drug demonstrated. new insight into mechanism epithelial uptake might provide basis future design with reduced toxicity.