Effects of thiabendazole (TBZ) on mitochondrial function in renal cortex of ICR mice
Introduction
Thiabendazole [2-(4′-thiazolyl)benzimidazole; TBZ] has broad anthelmintic activity and is effective in the treatment of various nematode infections in human and animals. It is also widely used as a fungicide in agriculture and the domestic environment.
Toxic effects of TBZ have been found in humans and animals. Intrahepatic cholestasis and haemat-uria or dark urine were reported in man after a course of thiabendazole therapy for parasitic infection (Davidson et al., 1988; Golden et al., 1974; Manivel et al., 1987; Pawlowski and Skrzypinska, 1972; Rex et al., 1983; Roy et al., 1989). Slight anaemia was observed in dogs given TBZ for 2 yr (Robinson et al., 1965) or rats given TBZ for 13 wk (Mikuriya et al., 1981). Subchronic (13 wk) administration of TBZ in the diet caused slight anaemia and liver or kidney injury in mice (Tada et al., 1996). TBZ induced reduction deformity of limbs in mice by oral administration on days 9 to 12 of gestation (Ogata et al., 1984). The incidence of urinary bladder tumours induced in rats by sodium o-phenyl-phenate (OPP-Na) was increased by the simultaneous administration of TBZ (Fujii et al., 1986).
We have investigated the effects of TBZ on the kidneys of mice. Single oral administration of TBZ caused polyuria, glucosuria, proteinuria (Tada et al., 1989), and significant increase of kidney weight and inhibition of organic ion uptake in renal slices (Tada et al., 1992). Using inducers (phenobarbital, β-naphthoflavone or 3-methylcholanthrene) or inhibitors (SKF-525A or piperonyl butoxide) of microsomal monooxygenase system, it was revealed that TBZ-induced renal tubular injury was correlated with blood levels of TBZ, not its metabolites (5-hydroxy TBZ or 2-acetylbenzimidazole) (Tada et al., 1992). This indicates that TBZ-induced renal injury may be attributed to the parent compound rather than its metabolites.
In our previous study (Tada et al., 1994), renal tubular necrosis, which may ultimately lead to death in mice, was first observed at 24 hours after dosing and was more numerous and extensive at 2 or 3 days after dosing. Also, serum urea nitrogen concentration, an indicator of renal function, was significantly elevated at 1 to 3 days after TBZ dosing (Tada et al., 1994). The studies on absorption, distribution and excretion of TBZ in mice revealed that the level of 14C-TBZ in plasma reached a maximum within 0.5 hr after dosing and then declined rapidly (Yoneyama et al., 1984). Tada et al. (1992)reported that TBZ in blood was not detected in mice at 24 hr after dosing. Thus, renal tubular necrosis and renal dysfunction developed after decline of TBZ concentration in blood. The biochemical responses in renal tubular cells within 24 hr after TBZ dosing seems to be important for understanding the mechanism for renal tubular necrosis. We have studied the structural alterations of mitochondria in renal proximal tubular cells at 24 hr after TBZ dosing (Tada et al., 1994). Mitochondria play an important role in production of energy to maintain cellular integrity. The purpose of the present study was to investigate the time course and dose–response relationships of toxicity and mitochondrial function in the early stages of TBZ nephrotoxicity.
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Chemicals and animals
Microfine TBZ (lot no. BZA 540; >98.5% pure) was purchased from Merck Sharp and Dohme International (Rahway, NJ, USA). All other chemicals used were reagent grade.
Crj:CD-1(ICR) male mice (Charles River Japan Inc, Kanagawa, Japan) were used at 11–12 wk old (34–41 g body weight). They were housed individually in plastic cages with wood chips and were given access ad lib. to water and standard pelleted chow CE-2 (Nihon Clea Co. Ltd, Tokyo, Japan). The animal room was kept under controlled
In vivo effects of TBZ on renal cortical mitochondrial respiration
Respiratory rates of mitochondria in renal cortex at 3, 6 or 16 hr after dosing of 0, 1000 or 2000 mg TBZ/kg body weight were shown in Fig. 1. At 3 hr after dosing, the state 3 respiratory rates, the state 4 respiratory rates and the DNP-uncoupled respiratory rates of renal cortical mitochondria from mice given 1000 or 2000 mg TBZ/kg body weight were not significantly different from those of control mice. At 6 hr after dosing, the state 3 respiratory rates of renal cortical mitochondria from mice
Discussion
A single oral administration of TBZ caused the necrosis of proximal convoluted tubular cells and swelling of mitochondria with fine granules and condensation of mitochondrial matrix in proximal tubular cells at 24 hr after dosing (Tada et al., 1994). However, little is known of the biochemical change provoked by TBZ in mitochondria of renal proximal tubular cells. Furthermore, to establish that mitochondrial injury by TBZ has in vivo significance in the development of nephrotoxicity, the effect
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