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Subcellular localization of celiptium-induced peroxidative damage in rat renal cortex

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Abstract

Celiptium (N2-methyl-9-hydroxyellipticinium) is an antitumor agent of the ellipticine series. We have shown a dose-dependent nephrotoxicity in rats and demonstrated a lipid overload in proximal tubular cells (unsaturated free fatty acid accumulation). We have also shown an increase in thiobarbituric acid reactive substances (TBARS), namely the 4-hydroxyalkenals, that is paralleled by a decrease in phosphatidylethanolamine in rat kidney cortex. In the present study, peroxidative damage was localized in mitochondria, microsomal and brush-border membranes of kidney cortex. Female Wistar rats were injected with a single i. v. dose of 20 mg/kg celiptium and sacrificed on day 8. Subcellular fractionation studies showed that celiptium induced alterations: 1) in mitochondria (slight increase in aldehydes), 2) in microsomal membranes (increase in free fatty acids (FFA) with in particular rises in oleic (18∶1) and linoleic (18∶2) acids), 3) in brush-border membranes or BBM (decrease in protein and phospholipid contents); residual membranes showed an increase in oleic and linoleic acids and a decrease in the polyunsaturated fatty acids, arachidonic (20∶4) and docosahexaenoic (22∶6) acids, 4) in cytosol (increase in FFA and TBARS content). Thus, celiptium induces peroxidative damage in kidneys through lipid abnormalities which predominantly occur in brush-border membranes and consist of an increase in free fatty acids and aldehydes in cytosol.

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Abbreviations

ARF:

acute renal failure

BBM:

brush-border membranes

TLC:

thin layer chromatography

HPTLC:

high performance thin layer chromatography

PC:

phosphatidylcholine

PE:

phosphatidyl-ethanolamine

PI:

phosphatidylinositol

PS:

phosphatidylserine

SPH:

sphingomyelin

FFA:

free fatty acids

TBARS:

thiobarbituric acid reactive substances

MDA:

malonaldehyde

NAG:

N-acetyl-B-d-glucosaminidase

γ-GT:

γ-glutamyl-transpeptidase

AAP:

alanine aminopeptidase

PLA2 :

phospholipase A2

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Authors and Affiliations

  1. UER Médecine-Pharmacie, INSERM 295, St-Etienne du Rouvray, F-76 800, France

    Gilda Raguenez-Viotte, Nathalie Thomas & Jean -Paul Fillastre

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  1. Gilda Raguenez-Viotte
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  2. Nathalie Thomas
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  3. Jean -Paul Fillastre
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Raguenez-Viotte, G., Thomas, N. & Fillastre, J.P. Subcellular localization of celiptium-induced peroxidative damage in rat renal cortex. Arch Toxicol 65, 244–251 (1991). https://doi.org/10.1007/BF02307316

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  • DOI: https://doi.org/10.1007/BF02307316

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