Stimulation of cyclophosphamide-induced pulmonary microsomal lipid peroxidation by oxygen.
Cyclophosphamide (CP) causes lung toxicity in a wide variety of animals including humans. Recent reports suggest that CP increases lipid peroxide formation in the lung, and that oxygen (O2) potentiates CP-induced lung toxicity. We hypothesized that CP, or one of its toxic metabolites, acrolein, stimulates lung lipid peroxide formation in the presence of high O2 tensions. To test this, rat lung microsomes were treated in vitro with CP or acrolein in the presence of NADPH and 0-100% O2 with and without superoxide dismutase (SOD), glutathione (GSH), dithiothreitol (DTT), and EDTA (agents which scavenge reactive O2 species and/or detoxify reactive metabolites). Lipid peroxide formation in untreated microsomes was increased 40, 39, and 37% in 60, 80 and 100% O2 respectively (P less than 0.02 vs. 21% O2 air). Lipid peroxide formation in microsomes treated with CP increased 2-3-fold under 21% O2 (P less than 0.05 vs. untreated under 21% O2). However, increases in lipid peroxide formation were 3-4 fold in CP treated microsomes under 40-100% O2 (P less than 0.001 vs. untreated at same % O2). CP and acrolein-stimulated lipid peroxidation with and without O2 exposure was significantly (P less than 0.05) reduced by prior addition of SOD, GSH, DTT, or EDTA to the lung microsomal suspension. These results indicate that lipid peroxide formation increases in CP and acrolein-treated lung microsomes, and high O2 tensions stimulate CP-induced lipid peroxidation. Stimulation of CP-induced microsomal lipid peroxidation appears to be mediated by reactive O2 species or metabolites.
D000171:Acrolein / Q000494:pharmacology; D000818:Animals; D003520:Cyclophosphamide / Q000633:toxicity*; D004357:Drug Synergism; D005978:Glutathione / Q000494:pharmacology; D066298:In Vitro Techniques; D008054:Lipid Peroxides / Q000096:biosynthesis*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D051381:Rats
D008054:Lipid Peroxides; D000171:Acrolein; D003520:Cyclophosphamide; D005978:Glutathione; D010100:Oxygen