Cyclophosphamide-induced lung toxicity: mechanism of endothelial cell injury.
Cyclophosphamide (CP) is associated with significant pulmonary toxicity; however, the mechanism of toxicity is unknown. An in vitro endothelial model of injury was developed to assess the direct toxic effects of CP, CP derivatives and CP metabolites on cultured endothelial cells. Injury to 51Cr-labeled bovine artery pulmonary endothelial (BPAE) cells was quantified by the release of 51Cr from BPAE cells incubated for 18 h with injury expressed as a cytotoxic index. Because CP activation and metabolism occurs primarily in liver, assays assessing CP effects were conducted in the presence of an hepatic microsomal enzyme system. Upon activation, CP produces 4-hydroxycyclophosphamide, acrolein (ACR) and the alkylating metabolite, phosphoramide mustard. Nonactivated CP demonstrated no toxicity to BPAE cells within 18 h; whereas, activated CP induced significant BPAE cell injury in a concentration-dependent manner. Specific metabolites of CP 4-hydroxycyclophosphamide and ACR were markedly more toxic to BPAE cells than phosphoramide mustard. Sulfhydryl-rich compounds, S-2-(3-aminopropylamino)ethylphosphoric acid (WR-2721) and N-acetylcysteine, significantly reduced 4-hydroxycyclophosphamide- and ACR-induced injury but had no significant protective effect against phosphoramide mustard-induced toxicity. These studies suggest 1) CP is not metabolized within pulmonary artery endothelial cells, 2) ACR may be the principal CP metabolite involved in mediating direct injury to pulmonary artery endothelial cells and 3) sulfhydryl-rich agents may be effective in reducing CP-induced damage to critical endothelial cell barriers.
Kachel
D L
DL
Department of Internal Medicine, Indiana University School of Medicine, Indianapolis.
Martin
W J
WJ
D000111:Acetylcysteine / Q000494:pharmacology; D004999:Amifostine / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D002417:Cattle; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000493:pharmacokinetics / Q000633:toxicity*; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects*; D008168:Lung / Q000187:drug effects*; D011651:Pulmonary Artery
D003520:Cyclophosphamide; D004999:Amifostine; D000111:Acetylcysteine