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Acute renal toxicity of thiabendazole (TBZ) in ICR mice
Y Tada1, T Fujitani, M Yoneyama
1Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan.
Abstract:
The acute toxic effects of thiabendazole [2-(4'-thiazolyl)benzimidazole; TBZ] on the kidneys of ICR mice were investigated. The mice were given 0, 250, 500 or 1000 mg TBZ/kg body weight by gavage (using olive oil as a vehicle), and the kidneys were subjected to pathological examination at 1, 3, 5 or 24 hr after dosing. Gross findings were slight enlargement and the presence of whitish areas (white maculae) in kidneys of treated mice at 3, 5 or 24 hr after dosing. Histological findings were desquamation of degenerated cells in proximal tubules of treated mice at 1 hr. Dilation of proximal, distal and collecting tubules was apparent in treated mice at 3, 5 and 24 hr. TBZ-induced renal injury was reduced by pretreatment with inducers of the microsomal monooxygenase system (sodium phenobarbital, beta-naphthoflavone and 3-methylcholanthrene) and were enhanced by pretreatment with inhibitors of that system (2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride and piperonyl butoxide). The concentration of TBZ in blood at 1 or 5 hr after dosing was lower in mice pretreated with microsomal monooxygenase system inducers and was higher in those pretreated with the inhibitors, than in those given TBZ alone. These results suggest that TBZ-induced renal injury may be attributable to the parent compound rather than its metabolites. Measurement of organic ion uptake into renal slices revealed significant depression of [1-14C]tetraethylammonium bromide (TEA) uptake in treated mice at 1 or 5 hr, whereas uptake of p-[glycyl-2-3H]aminohippurate (PAH) was not depressed at 1 or 5 hr after dosing. The reduction in uptake of TEA is interpreted as the result of competitive suppression of the tubular transport of TEA by TBZ. TBZ-induced renal injury was reduced by organic cation transport inhibitors [N'-methylnicotinamide (NMN) or thiamine] but not by organic anion transport inhibitor [p-(dipropylsulphamyl)benzoic acid probenecid], suggesting that the reduction of TBZ-induced renal injury is the result of competitive suppression of the tubular transport of TBZ by NMN or thiamine.
Insights
Thiabendazole (TBZ) causes acute kidney injury in mice, primarily due to the parent compound, not metabolites. This renal injury is linked to the competitive suppression of organic cation transport in kidney tubules.
Area of Science:
- Toxicology
- Nephrology
- Pharmacology
Background:
- Thiabendazole (TBZ) is an anthelmintic drug with known toxicities.
- Understanding the specific mechanisms of TBZ-induced kidney damage is crucial for risk assessment.
Purpose of the Study:
- To investigate the acute toxic effects of TBZ on mouse kidneys.
- To elucidate the role of metabolic activation and renal tubular transport in TBZ nephrotoxicity.
Main Methods:
- Administration of varying doses of TBZ to ICR mice.
- Pathological examination of kidneys at different time points post-dosing.
- Assessment of TBZ blood concentrations and renal organic ion transport (TEA and PAH).
- Evaluation of the effects of microsomal enzyme inducers/inhibitors and transport inhibitors on TBZ toxicity.
Main Results:
- TBZ caused dose-dependent renal injury, including tubular degeneration and dilation.
- Nephrotoxicity was modulated by microsomal monooxygenase system activity, suggesting a role for metabolism.
- However, results indicated the parent TBZ compound, rather than metabolites, is likely responsible for direct renal injury.
- TBZ significantly inhibited organic cation (TEA) uptake, but not organic anion (PAH) uptake, in renal slices.
- Organic cation transport inhibitors (NMN, thiamine) reduced TBZ-induced renal injury, supporting competitive inhibition of TBZ tubular transport.
Conclusions:
- Acute TBZ exposure induces significant nephrotoxicity in mice.
- The parent TBZ compound directly interferes with organic cation transport in renal tubules.
- This competitive inhibition of tubular transport is a key mechanism underlying TBZ-induced renal injury.
