Protective effect of calcium channel blockers against hexachlorobutadienenephrotoxicity in rat

ABSTRACT

Hexachlorobutadiene [HCBD] is a potent nephrotoxine in rodents. Its toxicity is due to its conjugation by glutathione [GSH] to form glutathione s-conjugate, by the enzyme glutathione S-transferase, and finally to the related cysteine-conjugate. This metabolite is then actively taken up by kidney and cleared in the renal tubular epithelial cells to a reactive thiol derivative, by the enzyme [3-lyase that covalently binds to the macromolecules. There are several studies regarding the protective effects of calcium channel blockers against some nephrotoxicants. Also our previous study showed that verapamil is able to protect the kidney against HCBD; therefore, in this study the protective effect of diltiazem and nifedipin [calcium blockers] against HCBD-induced nephrotoxicity in rat was examined.In this study, W/A rats from either sex were divided in 6 groups. Group one dosed with corn oil [1 ml/kg, i/p], group two dosed with HCBD [50mg/kg, i.p], and groups 3 to 6 dosed with [50 and/or 100microg/kg, i.p] diltiazem and nifedipine one hour before HCBD [50mg/kg] as single dose. After 24 hours, all animals were killed; blood samples were taken by cardiac puncture for measuring urea and creatinin. The kidneys were removed and fixed in formalin for histopathologic examination,. Concentration of urea as a marker of kidney damage, in group two [66.3 +/- 15.3mg/dl] was significantly higher than all other groups [33.8 +/- 3.2, 29.3 +/- 8.1, 29.3 +/- 9.2, 26.5±4, 33.8 +/- 3.8mg/dl] for control and groups 3-6 respectively. Also concentration of creatinin in group two [1.08 +/- 0.3 mg/dl] was significantly higher than all other groups [0.53 +/- 0.05, 0.57 +/- 0.06, 0.57 +/- 0.06, 0.53 +/- 0.05, 0.53 +/- 0.05mg/dl] for control and groups 3-6 respectively. Microscopic studies showed that there was substantial necrosis in the straight portion of the proximal tubules in HCBD-treated group. In the calcium-blocker treated groups, the renal proximal tubules showed a normal appearance and no damage were observed. In conclusion, diltiazem and nifedipine are able to protect the kidney against toxic effect of HCBD in rat