title: Adriamycin affects glomerular renal function: evidence for the involvement of oxygen radicals.
abstract: The early nephrotoxic effect of the antitumor drug adriamycin (ADR) is suggested to be related to the generation of oxygen free radicals. Therefore the O2-dependence and the influence of free radical scavengers were studied in the model of the isolated perfused single glomerulus of Myxine glutinosa and by histochemical demonstration of the glomerular ATP-ase. In Myxine, the glomerular ATP-ase activity was decreased after injection of ADR (5 mg/kg, i.v.). Both ADR-treated Myxine and controls were exposed for 48 h to an artificial atmosphere of 20% O2/80% N2 or 80% O2/20% N2, respectively. After 10 days a significant decrease of the hydraulic conductivity (k) was measured in the experimental group exposed to 80% O2 (k-values expressed as nl/s.mm Hg.mm2: controls (7): 0.059 +/- 0.017; ADR (7): 0.033 +/- 0.026). The reduction of k following the administration of ADR (20 mg/kg) could be prevented by the sulphydryl donor N-acetylcysteine (NAC). The sieving coefficient for albumin (phi) was significantly increased in ADR-treated animals, showing no O2-dependence (phi x 10(-2): controls (7) 1.3 +/- 0.2; ADR 20% O2 (8): 8.1 +/- 9.6; ADR 80% O2 (7): 6.9 +/- 6.7). phi was not affected by NAC. The lipid peroxide levels in liver, kidney and heart of Myxine increased after the administration of ADR, peaking by day 2 to 5. The circulation disorders of ADR-treated Myxine were not due to an accumulation of the drug in the heart, but rather to a lack of the intracellular antioxidant glutathione. It is concluded that the early nephrotoxic effect of ADR, as reflected by a decreased glomerular ATP-ase activity, is mediated by free radical formation. Oxidative stress on membrane compounds seems to reduce the water permeability of the glomerular barrier, while the ADR-induced sieving defect may be due to oxygen independent pathological mechanisms.
authors.affiliation: Department of Nephrology, Medical School Hannover, FRG.
authors.forename: M M
authors.initials: MM
authors.lastname: Barbey
authors.forename: L M
authors.initials: LM
authors.lastname: Fels
authors.forename: M
authors.initials: M
authors.lastname: Soose
authors.forename: K
authors.initials: K
authors.lastname: Poelstra
authors.forename: W
authors.initials: W
authors.lastname: Gwinner
authors.forename: W
authors.initials: W
authors.lastname: Bakker
authors.forename: H
authors.initials: H
authors.lastname: Stolte
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D004317:Doxorubicin / Q000633:toxicity*; D005609:Free Radicals; D006196:Hagfishes; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007674:Kidney Diseases / Q000139:chemically induced; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000201:enzymology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*; D010477:Perfusion
chemical_list: D005609:Free Radicals; D004317:Doxorubicin; D000251:Adenosine Triphosphatases; D010100:Oxygen