Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects (9): Protective effect of inositol hexasulfate against tobramycin-induced nephrotoxicity.
We examined the protective effect of inositol hexasulfate (IS6) against tobramycin (TOB)-induced nephrotoxicity. In the electrophoretic analysis, TOB alone and IS6 alone were observed as single spots on the cathode and anode sides, respectively. However, in the mixture of TOB and IS6 preincubated at 37 degrees C for 3 hr, the tailing of the spots of TOB and IS6 were observed from the origin to the cathode and the anode sides, respectively, and the overlapping of the spots of TOB and IS6 was recognized at the origin. These results indicated that TOB directly interacted with IS6 in vitro. Assay of TOB binding to rat kidney brush border membranes (BBMs) indicated that IS6 inhibited the binding of TOB to BBMs through an interaction of TOB and IS6. No significant reduction in intrarenal TOB level was observed in the rats given TOB (90 mg/kg, s.c.) and IS6 (153 or 610 mg/kg, s.c.). However, the treatment of rats with a combination of TOB and IS6 reduced the degree of necrosis of renal tubular cells and also suppressed the increases in urinary protein, urinary enzyme activities, blood urea nitrogen and plasma creatinine induced by TOB. Additionally, we detected a complex of TOB and IS6 in the urine of rats given both compounds simultaneously. These results indicate that IS6 protects against TOB-induced nephrotoxicity and that the protective action of IS6 may be due to the inhibition of TOB binding to BBMs through an interaction of TOB with IS6.
Kojima
R
R
Department of Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Ito
M
M
Suzuki
Y
Y
D000818:Animals; D000900:Anti-Bacterial Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001806:Blood Urea Nitrogen; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003404:Creatinine / Q000097:blood; D004588:Electrophoresis, Cellulose Acetate; D007294:Inositol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014031:Tobramycin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*
D000900:Anti-Bacterial Agents; C013063:inositol hexasulfate; D007294:Inositol; D003404:Creatinine; D014031:Tobramycin