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Monica A. Valentovic - One of the best experts on this subject based on the ideXlab platform.
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Cephaloridine in vitro toxicity and accumulation in renal slices from normoglycemic and diabetic rats.
Fundamental and applied toxicology : official journal of the Society of Toxicology, 1997Co-Authors: Monica A. Valentovic, John G. Ball, Bethany A. Rogers, M.kathleen Meadows, R. Christopher Harmon, Joshua MolesAbstract:Previous work has shown a reduction in Cephaloridine nephrotoxicity in a diabetic rat model. The following studies examined in vitro Cephaloridine toxicity in renal slices from normoglycemic and diabetic Fischer 344 rats. Diabetes was induced by acute intraperitoneal injection of 35 mg/kg streptozotocin. Renal cortical slices were isolated from normoglycemic and diabetic animals. Tissues were exposed to 0-5 mM Cephaloridine for 15-120 min. Pyruvate-directed gluconeogenesis was diminished in all groups exposed to 2-5 mM Cephaloridine for 60-120 min. Leakage of lactate dehydrogenase (LDH) was apparent only in the normoglycemic group in the presence of 4-5 mM Cephaloridine for 120 min. LDH leakage was not increased at any Cephaloridine concentration in the diabetic tissue. Total glutathione levels were compared in renal cortical slices exposed to Cephaloridine for 30-120 min. Baseline values for glutathione were comparable between normoglycemic and diabetic tissue suggesting that the mechanism for reduced toxicity was not due to higher glutathione levels in diabetic tissue. Total glutathione levels were diminished more rapidly in normoglycemic than diabetic tissue by incubation with 5 mM Cephaloridine. Comparison of Cephaloridine accumulation indicated that diabetic tissue accumulated less Cephaloridine than the normoglycemic group when tissues were incubated with 0-2 mM Cephaloridine. However, renal slice accumulation was similar between normoglycemic and diabetic groups following in vitro incubation with 4-5 mM Cephaloridine. These results suggest that the mechanism for reduced in vitro Cephaloridine toxicity in diabetic tissue cannot be limited to differences in accumulation and must include an unidentified cellular component.
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Comparison of Cephaloridine renal accumulation and urinary excretion between normoglycemic and diabetic animals.
Toxicology, 1996Co-Authors: Monica A. Valentovic, John G. Ball, Bethany A. RogersAbstract:The renal toxicity of Cephaloridine is reduced in a streptozotocin diabetic rat model. This study tested the hypothesis that renal cortical Cephaloridine accumulation was diminished in diabetic rats. The following studies also investigated whether renal excretion was enhanced in diabetic rats. Male Fischer 344 rats were randomly divided into normoglycemic or diabetic groups. Diabetes was induced by injection (intraperitoneal, i.p.) of 35 mg/kg streptozotocin. Normoglycemic and diabetic rats were injected (i.p.) with 1500 mg/kg Cephaloridine. Peak plasma Cephaloridine levels were similar in both groups. Renal cortical accumulation was diminished (P < 0.05) in the diabetic group 1 and 4 h after Cephaloridine injection. Urinary Cephaloridine excretion was enhanced (P < 0.05) in the diabetic group relative to the normoglycemic animals during the first 4 h after Cephaloridine injection. Comparisons between normoglycemic and diabetic groups indicated renal cortical Cephaloridine accumulation was lower in the diabetic group. These findings would support the hypothesis that reduced Cephaloridine toxicity in diabetic animals was due to reduced renal cortical accumulation of the toxin. These data also demonstrate that Cephaloridine excretion was enhanced in the diabetic group and may contribute to the diminished renal accumulation.
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Cephaloridine nephrotoxicity in diabetic rats: modulation by insulin treatment
Toxicology, 1995Co-Authors: Monica A. Valentovic, John G. BallAbstract:Previous studies have indicated that Cephaloridine nephrotoxicity was reduced in diabetic rats. This study determined whether the reduction in toxicity was due to streptozotocin or the diabetic state. Male Fischer-344 rats were injected intraperitoneally with 35 mg/kg streptozotocin to induce diabetes. Insulin (5 U/day, subcutaneously) was begun within 72 h and continued for 10 days. Toxicity was quantitated 48 h after injection of Cephaloridine (1500 mg/kg, i.p.) in normoglycemic (NC), diabetic (DC) and diabetic animals treated with insulin (DIC). Cephaloridine produced diuresis, glucosuria, proteinuria, elevated kidney weight and decreased renal cortical slice accumulation of organic ions in the NC group. Cephaloridine toxicity was reduced in the DC group since kidney weight, BUN level and renal cortical slice accumulation of organic anions were similar between treated and control animals. Cephaloridine treatment of the DIC group was associated with increased BUN levels, proteinuria and diminished renal cortical slice accumulation of organic cations. These results indicated that the diabetic state, and not streptozotocin, reduced Cephaloridine nephrotoxicity.
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Comparative studies of in vitro renal Cephaloridine toxicity between normoglycemic and diabetic rats.
Journal of applied toxicology : JAT, 1992Co-Authors: Monica A. Valentovic, John G. Ball, William R. Jeffrey, Dianne A. Bailly, Mario Morenas, Jack KinderAbstract:This study investigated if the attenuation in Cephaloridine toxicity associated with streptozotocin (STZ)-induced diabetes can be attributed to a direct cellular effect. Comparative studies examined the direct toxicity of Cephaloridine 14 days after (35 mg kg-1, i.p.) STZ or vehicle injection of male Fischer 344 (F344) rats. In vitro Cephaloridine toxicity was assessed by measuring lipid peroxidation, renal gluconeogenesis and organic ion accumulation in renal cortical slices. The in vitro toxicity of Cephaloridine was reduced in the diabetic group since lipid peroxidation was not increased following a 120-min exposure to Cephaloridine. This was in contrast to a concentration- and time-dependent increase in lipid peroxidation in renal tissue derived from normoglycemic animals pre-incubated with 0-5 mM Cephaloridine. Renal gluconeogenesis was inhibited in a concentration-dependent manner in the normoglycemic group following a 15-90-min exposure to 0-5 mM Cephaloridine. Pyruvate-stimulated gluconeogenesis was diminished in the diabetic group only after a 90-min preincubation. Renal cortical slice accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA) was decreased in the normoglycemic group. Accumulation of TEA, but not PAH, was decreased (P less than 0.05) in the diabetic group. These results indicate that in vitro Cephaloridine toxicity was attenuated by STZ-induced diabetes.
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Contribution of acetone and osmotic-diuresis by streptozotocin-induced diabetes in attenuation of Cephaloridine nephrotoxicity.
Toxicology, 1992Co-Authors: Monica A. Valentovic, John G. Ball, Dianne K. AnestisAbstract:Previous studies have indicated that Cephaloridine nephrotoxicity was reduced in streptozotocin (STZ)-induced diabetic rats. Experiments were performed to investigate if a shorter duration of diabetes would reduce Cephaloridine nephrotoxicity. Studies were also conducted to examine the contribution of osmotic diuresis and ketone accumulation to the mechanism for reduced toxicity. Male Fischer 344 (F344) rats were injected with 30 mg/kg STZ or vehicle. Seven days after STZ or vehicle administration, the animals were treated (i.p.) with 1500 mg/kg Cephaloridine. Increased kidney weight, blood urea nitrogen (BUN) level and decreased renal cortical slice accumulation of p-aminohippurate (PAH) and tetraethyl-ammonium (TEA) were measured in the normoglycemic group. No differences in renal function were detected between diabetic groups treated with Cephaloridine or vehicle (PFC). Pretreatment of euglycemic rats with 0 or 10% dextrose in the drinking water and by oral gavage failed to prevent the renal damage produced by 1500 mg/kg Cephaloridine despite glucosuria and urine output comparable to diabetic animals. However, dextrose-diuresis afforded a slight reduction in toxicity as indicated by changes in kidney weight and renal cortical slice accumulation of PAH and TEA. Pretreatment (oral) with 0 or 1.5 ml/kg acetone had no effect on Cephaloridine toxicity (1000 mg/kg, i.p.). These findings suggested that attenuation of Cephaloridine toxicity may be independent of the duration of diabetes. These results also indicated that glucose-mediated osmotic diuresis and acetone accumulation cannot account for reduced Cephaloridine toxicity in diabetic rats.
John G. Ball - One of the best experts on this subject based on the ideXlab platform.
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Cephaloridine in vitro toxicity and accumulation in renal slices from normoglycemic and diabetic rats.
Fundamental and applied toxicology : official journal of the Society of Toxicology, 1997Co-Authors: Monica A. Valentovic, John G. Ball, Bethany A. Rogers, M.kathleen Meadows, R. Christopher Harmon, Joshua MolesAbstract:Previous work has shown a reduction in Cephaloridine nephrotoxicity in a diabetic rat model. The following studies examined in vitro Cephaloridine toxicity in renal slices from normoglycemic and diabetic Fischer 344 rats. Diabetes was induced by acute intraperitoneal injection of 35 mg/kg streptozotocin. Renal cortical slices were isolated from normoglycemic and diabetic animals. Tissues were exposed to 0-5 mM Cephaloridine for 15-120 min. Pyruvate-directed gluconeogenesis was diminished in all groups exposed to 2-5 mM Cephaloridine for 60-120 min. Leakage of lactate dehydrogenase (LDH) was apparent only in the normoglycemic group in the presence of 4-5 mM Cephaloridine for 120 min. LDH leakage was not increased at any Cephaloridine concentration in the diabetic tissue. Total glutathione levels were compared in renal cortical slices exposed to Cephaloridine for 30-120 min. Baseline values for glutathione were comparable between normoglycemic and diabetic tissue suggesting that the mechanism for reduced toxicity was not due to higher glutathione levels in diabetic tissue. Total glutathione levels were diminished more rapidly in normoglycemic than diabetic tissue by incubation with 5 mM Cephaloridine. Comparison of Cephaloridine accumulation indicated that diabetic tissue accumulated less Cephaloridine than the normoglycemic group when tissues were incubated with 0-2 mM Cephaloridine. However, renal slice accumulation was similar between normoglycemic and diabetic groups following in vitro incubation with 4-5 mM Cephaloridine. These results suggest that the mechanism for reduced in vitro Cephaloridine toxicity in diabetic tissue cannot be limited to differences in accumulation and must include an unidentified cellular component.
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Comparison of Cephaloridine renal accumulation and urinary excretion between normoglycemic and diabetic animals.
Toxicology, 1996Co-Authors: Monica A. Valentovic, John G. Ball, Bethany A. RogersAbstract:The renal toxicity of Cephaloridine is reduced in a streptozotocin diabetic rat model. This study tested the hypothesis that renal cortical Cephaloridine accumulation was diminished in diabetic rats. The following studies also investigated whether renal excretion was enhanced in diabetic rats. Male Fischer 344 rats were randomly divided into normoglycemic or diabetic groups. Diabetes was induced by injection (intraperitoneal, i.p.) of 35 mg/kg streptozotocin. Normoglycemic and diabetic rats were injected (i.p.) with 1500 mg/kg Cephaloridine. Peak plasma Cephaloridine levels were similar in both groups. Renal cortical accumulation was diminished (P < 0.05) in the diabetic group 1 and 4 h after Cephaloridine injection. Urinary Cephaloridine excretion was enhanced (P < 0.05) in the diabetic group relative to the normoglycemic animals during the first 4 h after Cephaloridine injection. Comparisons between normoglycemic and diabetic groups indicated renal cortical Cephaloridine accumulation was lower in the diabetic group. These findings would support the hypothesis that reduced Cephaloridine toxicity in diabetic animals was due to reduced renal cortical accumulation of the toxin. These data also demonstrate that Cephaloridine excretion was enhanced in the diabetic group and may contribute to the diminished renal accumulation.
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Cephaloridine nephrotoxicity in diabetic rats: modulation by insulin treatment
Toxicology, 1995Co-Authors: Monica A. Valentovic, John G. BallAbstract:Previous studies have indicated that Cephaloridine nephrotoxicity was reduced in diabetic rats. This study determined whether the reduction in toxicity was due to streptozotocin or the diabetic state. Male Fischer-344 rats were injected intraperitoneally with 35 mg/kg streptozotocin to induce diabetes. Insulin (5 U/day, subcutaneously) was begun within 72 h and continued for 10 days. Toxicity was quantitated 48 h after injection of Cephaloridine (1500 mg/kg, i.p.) in normoglycemic (NC), diabetic (DC) and diabetic animals treated with insulin (DIC). Cephaloridine produced diuresis, glucosuria, proteinuria, elevated kidney weight and decreased renal cortical slice accumulation of organic ions in the NC group. Cephaloridine toxicity was reduced in the DC group since kidney weight, BUN level and renal cortical slice accumulation of organic anions were similar between treated and control animals. Cephaloridine treatment of the DIC group was associated with increased BUN levels, proteinuria and diminished renal cortical slice accumulation of organic cations. These results indicated that the diabetic state, and not streptozotocin, reduced Cephaloridine nephrotoxicity.
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Comparative studies of in vitro renal Cephaloridine toxicity between normoglycemic and diabetic rats.
Journal of applied toxicology : JAT, 1992Co-Authors: Monica A. Valentovic, John G. Ball, William R. Jeffrey, Dianne A. Bailly, Mario Morenas, Jack KinderAbstract:This study investigated if the attenuation in Cephaloridine toxicity associated with streptozotocin (STZ)-induced diabetes can be attributed to a direct cellular effect. Comparative studies examined the direct toxicity of Cephaloridine 14 days after (35 mg kg-1, i.p.) STZ or vehicle injection of male Fischer 344 (F344) rats. In vitro Cephaloridine toxicity was assessed by measuring lipid peroxidation, renal gluconeogenesis and organic ion accumulation in renal cortical slices. The in vitro toxicity of Cephaloridine was reduced in the diabetic group since lipid peroxidation was not increased following a 120-min exposure to Cephaloridine. This was in contrast to a concentration- and time-dependent increase in lipid peroxidation in renal tissue derived from normoglycemic animals pre-incubated with 0-5 mM Cephaloridine. Renal gluconeogenesis was inhibited in a concentration-dependent manner in the normoglycemic group following a 15-90-min exposure to 0-5 mM Cephaloridine. Pyruvate-stimulated gluconeogenesis was diminished in the diabetic group only after a 90-min preincubation. Renal cortical slice accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA) was decreased in the normoglycemic group. Accumulation of TEA, but not PAH, was decreased (P less than 0.05) in the diabetic group. These results indicate that in vitro Cephaloridine toxicity was attenuated by STZ-induced diabetes.
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Contribution of acetone and osmotic-diuresis by streptozotocin-induced diabetes in attenuation of Cephaloridine nephrotoxicity.
Toxicology, 1992Co-Authors: Monica A. Valentovic, John G. Ball, Dianne K. AnestisAbstract:Previous studies have indicated that Cephaloridine nephrotoxicity was reduced in streptozotocin (STZ)-induced diabetic rats. Experiments were performed to investigate if a shorter duration of diabetes would reduce Cephaloridine nephrotoxicity. Studies were also conducted to examine the contribution of osmotic diuresis and ketone accumulation to the mechanism for reduced toxicity. Male Fischer 344 (F344) rats were injected with 30 mg/kg STZ or vehicle. Seven days after STZ or vehicle administration, the animals were treated (i.p.) with 1500 mg/kg Cephaloridine. Increased kidney weight, blood urea nitrogen (BUN) level and decreased renal cortical slice accumulation of p-aminohippurate (PAH) and tetraethyl-ammonium (TEA) were measured in the normoglycemic group. No differences in renal function were detected between diabetic groups treated with Cephaloridine or vehicle (PFC). Pretreatment of euglycemic rats with 0 or 10% dextrose in the drinking water and by oral gavage failed to prevent the renal damage produced by 1500 mg/kg Cephaloridine despite glucosuria and urine output comparable to diabetic animals. However, dextrose-diuresis afforded a slight reduction in toxicity as indicated by changes in kidney weight and renal cortical slice accumulation of PAH and TEA. Pretreatment (oral) with 0 or 1.5 ml/kg acetone had no effect on Cephaloridine toxicity (1000 mg/kg, i.p.). These findings suggested that attenuation of Cephaloridine toxicity may be independent of the duration of diabetes. These results also indicated that glucose-mediated osmotic diuresis and acetone accumulation cannot account for reduced Cephaloridine toxicity in diabetic rats.
Bethany A. Rogers - One of the best experts on this subject based on the ideXlab platform.
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Cephaloridine in vitro toxicity and accumulation in renal slices from normoglycemic and diabetic rats.
Fundamental and applied toxicology : official journal of the Society of Toxicology, 1997Co-Authors: Monica A. Valentovic, John G. Ball, Bethany A. Rogers, M.kathleen Meadows, R. Christopher Harmon, Joshua MolesAbstract:Previous work has shown a reduction in Cephaloridine nephrotoxicity in a diabetic rat model. The following studies examined in vitro Cephaloridine toxicity in renal slices from normoglycemic and diabetic Fischer 344 rats. Diabetes was induced by acute intraperitoneal injection of 35 mg/kg streptozotocin. Renal cortical slices were isolated from normoglycemic and diabetic animals. Tissues were exposed to 0-5 mM Cephaloridine for 15-120 min. Pyruvate-directed gluconeogenesis was diminished in all groups exposed to 2-5 mM Cephaloridine for 60-120 min. Leakage of lactate dehydrogenase (LDH) was apparent only in the normoglycemic group in the presence of 4-5 mM Cephaloridine for 120 min. LDH leakage was not increased at any Cephaloridine concentration in the diabetic tissue. Total glutathione levels were compared in renal cortical slices exposed to Cephaloridine for 30-120 min. Baseline values for glutathione were comparable between normoglycemic and diabetic tissue suggesting that the mechanism for reduced toxicity was not due to higher glutathione levels in diabetic tissue. Total glutathione levels were diminished more rapidly in normoglycemic than diabetic tissue by incubation with 5 mM Cephaloridine. Comparison of Cephaloridine accumulation indicated that diabetic tissue accumulated less Cephaloridine than the normoglycemic group when tissues were incubated with 0-2 mM Cephaloridine. However, renal slice accumulation was similar between normoglycemic and diabetic groups following in vitro incubation with 4-5 mM Cephaloridine. These results suggest that the mechanism for reduced in vitro Cephaloridine toxicity in diabetic tissue cannot be limited to differences in accumulation and must include an unidentified cellular component.
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Comparison of Cephaloridine renal accumulation and urinary excretion between normoglycemic and diabetic animals.
Toxicology, 1996Co-Authors: Monica A. Valentovic, John G. Ball, Bethany A. RogersAbstract:The renal toxicity of Cephaloridine is reduced in a streptozotocin diabetic rat model. This study tested the hypothesis that renal cortical Cephaloridine accumulation was diminished in diabetic rats. The following studies also investigated whether renal excretion was enhanced in diabetic rats. Male Fischer 344 rats were randomly divided into normoglycemic or diabetic groups. Diabetes was induced by injection (intraperitoneal, i.p.) of 35 mg/kg streptozotocin. Normoglycemic and diabetic rats were injected (i.p.) with 1500 mg/kg Cephaloridine. Peak plasma Cephaloridine levels were similar in both groups. Renal cortical accumulation was diminished (P < 0.05) in the diabetic group 1 and 4 h after Cephaloridine injection. Urinary Cephaloridine excretion was enhanced (P < 0.05) in the diabetic group relative to the normoglycemic animals during the first 4 h after Cephaloridine injection. Comparisons between normoglycemic and diabetic groups indicated renal cortical Cephaloridine accumulation was lower in the diabetic group. These findings would support the hypothesis that reduced Cephaloridine toxicity in diabetic animals was due to reduced renal cortical accumulation of the toxin. These data also demonstrate that Cephaloridine excretion was enhanced in the diabetic group and may contribute to the diminished renal accumulation.
Bernard Ferrier - One of the best experts on this subject based on the ideXlab platform.
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Identification of novel targets of Cephaloridine in rabbit renal proximal tubules synthesizing glutamine from alanine
Archives of toxicology, 2005Co-Authors: Jérôme Guitton, Agnès Conjard, Assaad A. Eid, Mireille Martin, Michelle Boghossian, Hélène Delage, Gabriel Baverel, Bernard FerrierAbstract:Cephaloridine, which accumulates in the renal proximal tubule, is a model compound used for studying the toxicity of antibiotics towards this nephron segment. Several studies have demonstrated that Cephaloridine alters renal intermediary and energy metabolism, but the mechanism by which this compound interferes with renal metabolic pathways remains incompletely understood. In an attempt to improve our knowledge in this field, we have studied the influence of Cephaloridine on the synthesis of glutamine, which represents a key metabolic process involving several important enzymatic steps in the rabbit kidney. For this, suspensions of rabbit renal proximal tubules were incubated for 90 and 180 min in the presence of 5 mM alanine, an important glutamine precursor, both in the absence and the presence of 10 mM Cephaloridine. Glutamate accumulation and glutamine synthesis were found to be inhibited by Cephaloridine after 90 and 180 min of incubation, and Cephaloridine accumulation in the renal proximal cells occurred in a time-dependent manner. The renal proximal tubule activities of alanine aminotransferase and glutamate dehydrogenase, which initiates alanine removal and releases the ammonia needed for glutamine synthesis, respectively, were inhibited to a significant degree and in a concentration-dependent manner by Cephaloridine concentrations in the range found to accumulate in the renal proximal cells. Citrate synthase and glutamine synthetase activities were also inhibited by Cephaloridine, but to a much lesser extent. The above enzymatic activities were not found to be inhibited when they were measured after successive dilutions of renal proximal tubules incubated for 180 min in the presence of 5 mM alanine and 10 mM Cephaloridine. When microdissected segments (S1-S3) of rabbit renal proximal tubules were incubated for 180 min with 5 mM alanine with and without 5 and 10 mM Cephaloridine, glutamate accumulation and glutamine synthesis were also inhibited in the three renal proximal segments studied; the latter Cephaloridine-induced inhibitions observed were concentration-dependent except for glutamine in the S3 segment. These results are consistent with the view that Cephaloridine accumulates and is toxic along the entire rabbit renal proximal tubule. They also demonstrate that Cephaloridine interferes in a concentration-dependent and reversible manner mainly with alanine aminotransferase and glutamate dehydrogenase, which are therefore newly-identified targets of the toxic effects of Cephaloridine in the rabbit renal proximal tubule.
Jack Kinder - One of the best experts on this subject based on the ideXlab platform.
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Comparative studies of in vitro renal Cephaloridine toxicity between normoglycemic and diabetic rats.
Journal of applied toxicology : JAT, 1992Co-Authors: Monica A. Valentovic, John G. Ball, William R. Jeffrey, Dianne A. Bailly, Mario Morenas, Jack KinderAbstract:This study investigated if the attenuation in Cephaloridine toxicity associated with streptozotocin (STZ)-induced diabetes can be attributed to a direct cellular effect. Comparative studies examined the direct toxicity of Cephaloridine 14 days after (35 mg kg-1, i.p.) STZ or vehicle injection of male Fischer 344 (F344) rats. In vitro Cephaloridine toxicity was assessed by measuring lipid peroxidation, renal gluconeogenesis and organic ion accumulation in renal cortical slices. The in vitro toxicity of Cephaloridine was reduced in the diabetic group since lipid peroxidation was not increased following a 120-min exposure to Cephaloridine. This was in contrast to a concentration- and time-dependent increase in lipid peroxidation in renal tissue derived from normoglycemic animals pre-incubated with 0-5 mM Cephaloridine. Renal gluconeogenesis was inhibited in a concentration-dependent manner in the normoglycemic group following a 15-90-min exposure to 0-5 mM Cephaloridine. Pyruvate-stimulated gluconeogenesis was diminished in the diabetic group only after a 90-min preincubation. Renal cortical slice accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA) was decreased in the normoglycemic group. Accumulation of TEA, but not PAH, was decreased (P less than 0.05) in the diabetic group. These results indicate that in vitro Cephaloridine toxicity was attenuated by STZ-induced diabetes.