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

Glycoprotein 330(gp330) isanendocytic receptor expressed intherenal proximal tubules andsomeotherabsorptive epithelia, e.g., intheinner ear. Thepresent study showsthat theantifibrinolytic polypeptide, aprotinin, andthenephroandototoxic antibiotics, aminoglycosides, andpolymyxin B compete forbinding of'"I-urokinase-pl asminogen activator inhibitor type-i complexes topurified rabbit gp330. Half maximal inhibition wasmeasured at4,uMforaprotinin, 50tiMforgentamicin, and0.5tiMforpolymyxin B.Drug binding togp330wasvalidated byequilibrium dialysis of [3H]gentamicin-gp330 incubations and binding/uptake studies inratproximal tubules andgp330-expressing L2 carcinoma cells. Analyses ofmutantaprotinins expressed in Saccharomyces cerevisiae revealed thatbasic residues are essential forthebinding togp330andrenal uptake. The polybasic drugs also antagonized ligand binding tothehumana2-macroglobulin receptor. However, therapidglomerular filtration ofthedrugs suggests kidney gp330 tobe thequantitatively mostimportant target. Inconclusion, anovel role ofgp330 asadrugreceptor isdemonstrated. Thenewinsight intothemechanism of epithelial uptake ofpolybasic drugs might provide abasis forfuture design ofdrugswithreduced toxicity. (J.Clin. Invest. 1995. 96:1404-1413.) Keywords: glycoprotein 330lowdensity lipoprotein receptor-related protein kidney aminoglycosides *endocytosis