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

Arch Toxicol. 1991;65(3):244-51. doi: 10.1007/BF02307316.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / toxicity*
  • Ellipticines / toxicity*
  • Fatty Acids / analysis
  • Female
  • Kidney Cortex / drug effects*
  • Kidney Cortex / metabolism
  • Kidney Cortex / ultrastructure
  • Lipid Peroxidation / drug effects*
  • Microsomes / chemistry
  • Microsomes / drug effects
  • Microvilli / chemistry
  • Microvilli / drug effects
  • Mitochondria / chemistry
  • Mitochondria / drug effects
  • Phospholipids / analysis
  • Proteins / analysis
  • Rats
  • Rats, Inbred Strains

Substances

  • Antineoplastic Agents
  • Ellipticines
  • Fatty Acids
  • Phospholipids
  • Proteins
  • elliptinium