Celiptium-induced nephrotoxicity and lipid peroxidation in rat renal cortex.
The antitumor drug celiptium, or N2-methyl-9-hydroxyellipticinium (NMHE), is an ellipticine derivative used in the treatment of breast cancer. Celiptium-induced dose-dependent renal toxicity in rats is characterized by tubular necrosis, tubulo-interstitial lesions and lipid overload in proximal tubular cells. Since biooxidative activation of celiptium occurs in kidney via highly electrophilic intermediates, we studied the effects of celiptium on rat renal cortex lipids in the context of lipid peroxidation damage. Female Wistar rats were injected with a single i.v. dose of 20 mg/kg celiptium and were killed on day 2, 4 or 8. Histochemical analysis of kidney sections detected Oil Red O (ORO)-positive deposits, whereas the same sections studied using Holczinger's copper rubeanic acid method showed free fatty acid (FFA) granules in renal tubular cells of celiptium-treated rats. Electron microscopy revealed large fatty droplets in proximal tubular cells. As creatinine clearance decreased on days 4 and 8, celiptium induced a significant increase in renal cortex FFA levels (6-fold increase over pretreatment values on day 8), whereas total glycerides increased 1.5 times. A 15% decrease in total phospholipids (PL) and a 50% decline in the mass of phosphatidylethanolamine (PE) were detected by lipid phosphorus assay. A 1.2-fold decrease in the unsaturation index of total PL was noted, with a significant decline in arachidonic acid (20:4). A 15% decrease in arachidonic content was observed in the fatty acid composition of PE. Analysis of the fatty acid composition of neutral lipids showed changes only in the FFA class. A great proportion of oleic (18:1) and linoleic (18:2) acids was found. Iodometric titration and thiobarbituric acid (TBA) reactivity detected respectively significant amounts of lipid hydroperoxides and TBA-reactive material in renal cortex lipid extracts on days 2, 4 and 8. The lipid-peroxidation process appeared to be involved in the pathogenesis of celiptium nephrotoxicity.
Dadoun
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C
INSERM U295, U.E.R. Medecine-Pharmacie de Rouen, Saint-Etienne-du-Rouvray, France.
Raguenez-Viotte
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G
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D004611:Ellipticines / Q000633:toxicity*; D005230:Fatty Acids, Nonesterified / Q000032:analysis; D005260:Female; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D010743:Phospholipids / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D004611:Ellipticines; D005230:Fatty Acids, Nonesterified; D010743:Phospholipids; C027767:elliptinium