Influence of streptozotocin (STZ)-induced diabetes, dextrose diuresis and acetone on cisplatin nephrotoxicity in Fischer 344 (F344) rats.
The following studies examined the impact of the diabetic state on cisplatin nephrotoxicity. This study also investigated the potential mechanisms for diabetes mediated reduction of cisplatin toxicity. A diabetic state was induced in male Fischer 344 (F344) rats after intraperitoneal (i.p.) injection of 27-35 mg/kg STZ. Cisplatin (5 mg/kg, i.p.) nephrotoxicity was examined in normoglycemic and diabetic rats after 48 and 96 h. Cisplatin was nephrotoxic within 96 h to normoglycemic animals as indicated by an increased kidney weight, marked elevations in serum BUN levels as well as significant P less than 0.05) decreases in renal cortical slice accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA). Cisplatin failed to depress renal cortical slice accumulation of PAH and TEA in the diabetic rats. Cisplatin was also less effective in increasing BUN levels or kidney weight in diabetic rats. Further studies investigated the impact of glycosuric diuresis and ketone bodies on cisplatin nephrotoxicity. Dextrose diuresis of normoglycemic rats failed to reduce the effect of cisplatin on BUN levels, kidney weight and renal cortical slice uptake of PAH and TEA. Acetone pretreatment of normoglycemic rats also did not reduce cisplatin nephrotoxicity. These results indicate: (1) cisplatin nephrotoxicity is attenuated in the experimental diabetic state, (2) diabetes does not reduce cisplatin nephrotoxicity through glycosuric diuresis and (3) ketone body accumulation does not modulate cisplatin nephrotoxicity.
Scott
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Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25755-9310.
Madan
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Valentovic
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MA
D000096:Acetone / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D016883:Diabetic Ketoacidosis / Q000378:metabolism / Q000473:pathology; D004231:Diuresis / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D007657:Ketone Bodies / Q000032:analysis; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009584:Nitrogen / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000378:metabolism; D014508:Urea / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000378:metabolism
D007657:Ketone Bodies; D013757:Tetraethylammonium Compounds; D000096:Acetone; D019789:Tetraethylammonium; D014508:Urea; D005947:Glucose; D009584:Nitrogen; D002945:Cisplatin; D010130:p-Aminohippuric Acid