Subcellular localization of celiptium-induced peroxidative damage in rat renal cortex.
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.
Raguenez-Viotte
G
G
INSERM 295, UER Médecine-Pharmacie, St-Etienne du Rouvray, France.
Thomas
N
N
Fillastre
J P
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D004611:Ellipticines / Q000633:toxicity*; D005227:Fatty Acids / Q000032:analysis; D005260:Female; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D015227:Lipid Peroxidation / Q000187:drug effects*; D008861:Microsomes / Q000737:chemistry / Q000187:drug effects; D008871:Microvilli / Q000737:chemistry / Q000187:drug effects; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects; D010743:Phospholipids / Q000032:analysis; D011506:Proteins / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D004611:Ellipticines; D005227:Fatty Acids; D010743:Phospholipids; D011506:Proteins; C027767:elliptinium