Biochemical indices of cyclophosphamide-induced lung toxicity.
Cyclophosphamide (CP) requires metabolic activation for its therapeutic action, and this metabolism results in the formation of two toxic metabolites, acrolein (ACR) and phosphoramide mustard (PM). To determine which metabolite is responsible for CP-induced lung injury, biochemical indices of toxicity and histopathologic changes in the lungs of CP-, ACR-, or PM-treated rats were evaluated. Experimental rats were given 200 mg kg-1 day-1 CP, 5 mg kg-1 day-1 ACR, or 50 mg kg-1 day-1 PM for 1 to 3 days, or were given 100 mg/kg CP for 1 day; control rats received vehicle alone for 1 to 3 days. Twenty-four hr after the last treatment the lungs were analyzed for (a) microsomal NADPH cytochrome c reductase and aniline hydroxylase activities; (b) microsomal lipid peroxide formation; and (c) glutathione content. In rats given 200 mg/kg CP, NADPH cytochrome c reductase and aniline hydroxylase activities decreased 66% (p less than 0.001) and 40% (p less than 0.001), respectively. Lipid peroxidation was increased 100 to 200% (p less than 0.001), and glutathione content was increased 60 to 70% (p less than 0.001). Similar but smaller changes were observed in the lungs of rats given 100 mg/kg CP. In rats given ACR, NADPH cytochrome c reductase and aniline hydroxylase activities decreased 66% (p less than 0.001) and 45% (p less than 0.001), and glutathione content increased 38% (p less than 0.05). In rats given PM, none of the biochemical variables examined were significantly altered. Phenobarbital and SKF 525-A prevented CP-induced biochemical alterations. Despite CP-induced biochemical alterations, no significant light microscopic changes were observed in the lungs. Alterations in lung mixed-function oxidase activity, GSH content, and microsomal lipid peroxide formation are early biochemical indices of CP-induced lung toxicity, and are due at least in part to the reactive metabolite ACR.
D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000032:analysis; D008054:Lipid Peroxides / Q000096:biosynthesis; D008168:Lung / Q000032:analysis / Q000187:drug effects*; D008297:Male; D008861:Microsomes / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D008054:Lipid Peroxides; D003520:Cyclophosphamide; D006899:Mixed Function Oxygenases; D000815:Aniline Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase; D005978:Glutathione; D010634:Phenobarbital