In vitro prediction of aminoglycoside ototoxicity.
The first step by which a basic aminoglycoside (AG) causes ototoxicity is thought to be electron binding to such acidic substances as phosphatidylinositol diphosphate and acidic glycosaminoglycans (AGAGs). We studied the competitive binding ability of AGs and basic dyes to AGAG in order to determine if this mechanism was indeed responsible for ototoxicity. The negative charge of heparin was the strongest among the AGAGs examined when the molar ratio of AG to AGAG was small. Toluidine blue was a better basic dye than acridine orange, methylene blue, alcian blue, or neutral red. After we mixed toluidine blue, heparin and an AG, the absorbance of free toluidine blue was measured at 625 nm. The difference in the free dye released by the well-established AG showed a fairly good correlation with the ototoxic activity found in vivo. However, the predicted ototoxicities of newly prepared AGs were greater than estimated when testing their effects on experimental animals. The basicity of AGs will determine their binding affinities to cochlear hair cell membranes and is an important factor in predicting ototoxicity.
D000617:Aminoglycosides / Q000009:adverse effects / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000378:metabolism; D004396:Coloring Agents; D004427:Ear Diseases / Q000139:chemically induced*; D006025:Glycosaminoglycans / Q000378:metabolism; D066298:In Vitro Techniques
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004396:Coloring Agents; D006025:Glycosaminoglycans