Abstract
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 (O 2) 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 O 2 tensions. To test this, rat lung microsomes were treated in vitro with CP or acrolein in the presence of NADPH and 0–100% O 2 with and without superoxide dismutase (SOD), glutathione (GSH), dithiothreitol (DTT), and EDTA (agents which scavenge reactive O 2 species and/or detoxify reactive metabolites). Lipid peroxide formation in untreated microsomes was increased 40, 39, and 37% in 60, 80 and 100% O 2 respectively ( P < 0.02 vs. 21% O 2 air). Lipid peroxide formation in microsomes treated with CP increased 2–3-fold under 21% O 2 ( P < 0.05 vs. untreated under 21% O 2). However, increases in lipid peroxide formation were 3–4 fold in CP treated microsomes under 40–100% O 2 ( P < 0.001 vs. untreated at same % O 2). CP and acrolein-stimulated lipid peroxidation with and without O 2 exposure was significantly ( P < 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 O 2 tensions stimulate CP-induced lipid peroxidation. Stimulation of CP-induced microsomal lipid peroxidation appears to be mediated by reactive O 2 species or metabolites.
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