Failure of inhibition of lipid peroxidation by vitamin E to protect against gentamicin nephrotoxicity in the rat.
We tested the hypothesis that accelerated lipid peroxidation, possibly at the level of the lysosome, is linked causally to the pathogenesis of aminoglycoside nephrotoxicity by investigating whether administration of vitamin E would inhibit lipid peroxidation and prevent or ameliorate gentamicin-induced proximal tubular cell injury. Five groups of rats were injected with either saline, vitamin E (600 mg/kg per day) for 6 days, gentamicin (100 mg/kg per day) for 6 days, vitamin E for 6 days plus gentamicin for 6 days or vitamin E for 12 days and gentamicin for the last 6 days. Gentamicin alone induced a 16% increase in renal cortical phospholipids; vitamin E had no significant effect on this change. Gentamicin alone caused accelerated lipid peroxidation evident by a doubling of renal cortical malondialdehyde to 1.23 nmol/mg protein, and a sharp decline of esterified polyunsaturated fatty acids, especially arachidonic acid which fell 43%. These changes were accompanied by depressions of superoxide dismutase, catalase, and total glutathione and a shift from reduced to oxidized glutathione. Concurrent treatment of rats with vitamin E plus gentamicin for 6 days had no significant effect on the gentamicin-induced alterations of malondialdehyde, superoxide dismutase, catalase or the glutathione cascade; however, the shift from polyunsaturated to saturated fatty acids was largely reversed. In rats pretreated with vitamin E for 6 days, gentamicin failed to raise renal cortical malondialdehyde above that of saline-treated rats. The changes in esterified fatty acids were prevented almost entirely, and there were no significant alterations from control of the glutathione cascade. The depressions of superoxide dismutase and of catalase, however, were not reversed. Vitamin E did not affect the amount of gentamicin accumulated in renal cortex nor did it prevent the gentamicin-induced rise of serum creatinine. Examination of renal cortex by light and electron microscopy revealed that vitamin E did not prevent or even reduce the severity of gentamicin-induced proximal tubular cell lesions and necrosis. These results confirm those we obtained in a previous study with the antioxidant diphenyl-phenylenediamine. The observation that inhibition of lipid peroxidation by two distinct antioxidants failed to prevent proximal tubular cell injury and renal dysfunction associated with gentamicin administration leads us to conclude that lipid peroxidation is a consequence and not a cause of gentamicin-induced nephrotoxicity.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005839:Gentamicins / Q000494:pharmacology / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D007687:Kidney Tubules, Proximal / Q000473:pathology; D008054:Lipid Peroxides / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology*
D001095:Arachidonic Acids; D005227:Fatty Acids; D005839:Gentamicins; D008054:Lipid Peroxides; D010743:Phospholipids; D014810:Vitamin E; D016718:Arachidonic Acid; D008315:Malondialdehyde; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione