Studies on the Nephrotoxicity of Aminoglycoside Antibiotics and Protection from These Effects (3) Protective Effect of Latamoxef against Tobramycin Nephrotoxicity and Its Protective Mechanism

Kojima, Ryoji; Ito, Mikio; Suzuki, Yoshio

doi:10.1254/jjp.42.397

Cited by 24 publications

(15 citation statements)

References 19 publications

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“…In addition, in vitro investigations have demonstrated that freshly isolated proximal tubular fragments are much less sensitive to the cytotoxic effects of ADR than isolated glomeruli (30,31 ). The dose chosen in this study caused minimal changes in urinary protein up to 35 days, after which time proteinuria became increasingly apparent.…”

Section: Histochemistrymentioning

confidence: 99%

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Enhanced Hexachloro-1:3-butadiene Nephrotoxicity in Rats with a Preexisting Adriamycin-Induced Nephrotic Syndrome

Kirby

Bach

1995

Toxicol Pathol

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Renal damage was assessed by histopathology and urinalysis in male Wistar rats treated with either hexachloro-1:3-butadiene (HCBD; a single 170-mg/kg ip dose that caused proximal tubule necrosis), adriamycin (ADR; a single 5-mg/kg ip dose that caused minimal glomerular changes up to 35 days), or HCBD given 2 wk after ADR and compared with age-matched control rats for 21 days. Urinalysis values in ADRtreated rats showed minimal renal changes. HCBD significantly elevated urine volume (10-fold), protein (5-fold), glucose (175-fold), and brush border enzymes (10-600-fold), indicating severe proximal tubular damage, but most parameters returned to pretreatment levels 6 days after treatment. In ADR-pretreated rats subsequently given HCBD, both the urinary alkaline phosphatase and the ratio of kidney : body weight were significantly higher for longer periods. Histopathology demonstrated that the HCBD-induced proximal tubular lesion was confined to the outer stripe of the outer medulla. Advanced regeneration and repair was evident 21 days after HCBD treatment. In the ADR-pretreated rats the HCBD-induced lesion was more severe and affected the entire cortex (24).Statistics. Statistically significant differences between groups were determined by 2-tailed Students' t-test, with p < 0.05 considered to be statistically significant. RESULTS UrinanalysisThere were no significant differences in the urinary parameters in the control and ADR groups ( (Fig. 1 a). Tubules were dilated and filled with homogenous eosinophilic material and necrotic epithelial cells. Signs of regeneration and restitution (i.e., tubular re-epithelialization and loss of tubular casts and debris) were evident by day 7 and complete 21 days after treatment (Fig. 1 b).Histologically, animals in the ADR/HCBD group showed much more extensive renal damage (Fig. 2a) when compared to those treated with HCBD alone (see Fig. 1 a). Extensive tubular damage was present throughout the entire cortex 2 days after HCBD treatment, and tubules were dilated and filled with homogeneous proteinaceous material. Sloughed necrotic calcified epithelial cells were observed in tubular lumens and casts extended deep into the medulla (Fig. 2b). Extensive calcification was evident by day 7 (which was not seen in the HCBD only group) and by day 21, regeneration, although apparent, was less advanced and marked tubular calcification was still evident (Fig. 2c). Table 2 summarizes the differences between the ADR/HCBD group and HCBD alone. HistochemistryControl kidneys demonstrated normal GGT staining of the tubular epithelium of the outer stripe of the outer medulla (Fig. 3a). ADR caused no changes in this staining pattern. GGT staining in the outer stripe of the outer medulla was diminished 24 hr after HCBD treatment, was barely evident by day 3 (Fig. 3b) HCBD is a useful model toxin for damaging the proximal tubule. It is metabolized in the liver, ex-

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Section: Histochemistrymentioning

confidence: 99%

“…For example, the potentiation of the nephrotoxic effect of aminoglycosides in combination with cephalosporin in humans has not been demonstrated in experimental animals (25,35). This is generally explained by the fact that laboratory animals do not have the underlying disease processes, which necessitate antibiotic administration (32 …”

Section: Histochemistrymentioning

confidence: 99%

Enhanced Hexachloro-1:3-butadiene Nephrotoxicity in Rats with a Preexisting Adriamycin-Induced Nephrotic Syndrome

Kirby

Bach

1995

Toxicol Pathol

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“…Urinary protein content and NAG activity, as well as BUN content, were measured as in our previous report (1). In addition to the measurements of biochemical parameters in the urine and blood, the histological observa tion of kidneys also was performed on the sections stained with Periodic Acid-Schiff (PAS) for light microscopy, as described pre viously (1 ).…”

Section: Methodsmentioning

confidence: 99%

“…We have already reported that latamoxef (LMOX), an oxacephem antibiotic, prevents tobramycin (TOB)-induced nephrotoxicity in rats and that the protective effect of LMOX is partly due to the ability of LMOX to reduce the intrarenal TOB concentration (1). We have found that the inhibitory effect of LMOX on intrarenal TOB level resulted from the inhi bition of the binding of TOB to renal brush border membranes (BBMs) (2) by a molecu lar interaction between TOB and LMOX (3).…”

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Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects. (8): Protective effect of pyridoxal-5'-phosphate against tobramycin nephrotoxicity.

1990

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Abstract-We investigated the effect of pyridoxal-5'-phosphate (PALP) on tobra mycin (TOB)-induced nephrotoxicity in rats. Paper electrophoretic analysis showed that in the mixture of TOB and PALP, the spot corresponding to TOB alone almost disappeared and the spot associated with TOB overlapped with that associated with PALP, although the spots of TOB alone and PALP alone were observed as single spots on the cathode and anode sides, respectively. The overlapping of both compounds indicated that TOB could directly interact with PALP in vitro. In the assay of TOB binding to renal brush border membranes (BBMs), PALP significantly inhibited the binding of TOB to BBMs by interacting with TOB outside of BBMs vesicles.Intrarenal TOB levels in rats receiving TOB and PALP were lower than those in rats given TOB alone.Combination with PALP markedly suppressed the urinary protein content, urinary N-acetyl-(3-D glucosaminidase activity and blood urea nitrogen content elevated by TOB, and also reduced the degree of TOB-induced renal tubular cell necrosis. These results indicate that PAL P protects the rat kidneys from TOB-induced nephrotoxicity and that the protective effect of PALP may be due to the reduced intrarenal TOB con centration and less binding of TOB to BBMs induced by the interaction of PALP with TO B.We have already reported that latamoxef (LMOX), an oxacephem antibiotic, prevents tobramycin (TOB)-induced nephrotoxicity in rats and that the protective effect of LMOX is partly due to the ability of LMOX to reduce the intrarenal TOB concentration (1). We have found that the inhibitory effect of LMOX on intrarenal TOB level resulted from the inhi bition of the binding of TOB to renal brush border membranes (BBMs) (2) by a molecu lar interaction between TOB and LMOX (3).From our previous study using LMOX, it was hypothesized that a compound which has a negative charge in its molecule and is excreted into the urine might prevent TOB induced nephrotoxicity by reducing the in trarenal TOB level and by inhibiting the bind ing of TOB to BBMs through a molecular interaction between TOB and the compound.As shown in Fig. 1, pyridoxal-5'-phosphate (PALP), an active form of vitamin B6, has a phosphate group in its molecule and is nega tively charged at physiological pH. PALP also has an aldehyde group, which can form a Schiff base by binding covalently to amino groups of TOB. In general, excess amounts of vitamins are excreted into the urine without converting them into metabolites, when large amounts of vitamins are administered. There fore, in the present study, to examine the ability of PALP to prevent TOB-induced nephrotoxicity, we designed experiments to monitor the following: 1) in vitro interaction of TOB with PALP, 2) the effect of PALP on TOB binding to BBMs, 3) the effect of PALP on intrarenal TOB concentration, and 4) the effect of PALP on the nephrotoxicity of TOB in vivo.In addition, in order to obtain some in formation about the mechanism of the action

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“…We have already reported that latamoxef (LMOX), which prevents tobramycin JOB) induced nephrotoxicity, reduced intrarenal TOB concentration (1). It has been suggested that aminoglycoside antibiotics (AGs) are ac cumulated into lysosomes by pinocytosis after the binding to renal brush border mem branes (BBMs) (2).…”

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confidence: 99%

Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects (7): Effect of latamoxef on binding of tobramycin to brush border membranes isolated from rat kidney cortex.

1989

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Abstract-We investigated the effect of latamoxef (LMOX) on the binding of tobramycin JOB) to brush border membranes (BBMs) isolated from rat kidney cortex by calcium precipitation.The simultaneous treatment with TOB (0.2 mM) and LMOX (10 and 20 mM) to the BBMs fraction (about 250 acg protein) sig nificantly inhibited the binding of TOB to BBMs. The addition of the reaction mixture of TOB (0.2 mM) and LMOX (4, 10 and 20 mM) which was preincubated for 3 hr at 37°C, to the BBMs fraction resulted in less binding of TOB to the mem branes than that observed in the case of simultaneous treatment with both drugs . Although [14C]-labeled LMOX was taken up by BBMs temperature and time dependently, the pretreatment with LMOX showed no obvious differences in inhibition of the TOB binding to BBMs, as compared with the result from simul taneous treatment with both drugs.Additionally, the binding of TOB to the LMOX treated BBMs that were resuspended in fresh medium after the pretreatment with LMOX for 10 min at 37°C was similar to that of TOB to the non-treated BBMs. These results indicate that LMOX inhibits the binding of TOB to BBMs not by binding to BBMs but by interacting with TOB.

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Studies on the Nephrotoxicity of Aminoglycoside Antibiotics and Protection from These Effects (3) Protective Effect of Latamoxef against Tobramycin Nephrotoxicity and Its Protective Mechanism

Cited by 24 publications

References 19 publications

Enhanced Hexachloro-1:3-butadiene Nephrotoxicity in Rats with a Preexisting Adriamycin-Induced Nephrotic Syndrome

Enhanced Hexachloro-1:3-butadiene Nephrotoxicity in Rats with a Preexisting Adriamycin-Induced Nephrotic Syndrome

Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects. (8): Protective effect of pyridoxal-5'-phosphate against tobramycin nephrotoxicity.

Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects (7): Effect of latamoxef on binding of tobramycin to brush border membranes isolated from rat kidney cortex.

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