© 1984 Oxford University Press
research-article |
Enhanced Oxygen Toxicity following Treatment with 1,3-Bis(2-chloroethyl)-1 -nitrosourea
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas Austin, Texas 78712-1074
Enhanced Oxygen Toxicity following Treatment with l,3-Bis(2-chloroethyi)-l-nitrosourea. Kehrer, J. P., AND PARAIDATHATHU, T. (1984). Fundam. Appl. Toxicol. 4, 760–l767. The anticancer drug l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) inhibits glutathione reductase, an enzyme involved in oxidant defense systems. The 30-day LD50 for BCNU in male and female BALB/c mice was 52 and 46 mg/kg, respectively. A 35-mg/kg BCNU dose was not lethal to any animal. Glutathione reductase was inhibited in lung tissue by about 50% for 4 days following a single 35 mg/kg dose of BCNU. The prolonged inhibition of glutathione reductase by BCNU suggested this drug might enhance pulmonary oxygen toxicity by diminishing the lung's antioxidant capacity. Exposing mice treated with 35 or 50 mg/kg BCNU to continuous 85% oxygen decreased the LT50 from 13.1 to 6.3 and 5.3 days, respectively, compared to vehicle-treated controls. All mice treated with 35 mg/kg BCNU or vehicle and exposed to 85% oxygen only on Days 0–4 survived to Day 30. Extending the hyperoxic exposure 1 additional day resulted in the death of all BCNU-treited mice, while 70% of the vehicle-treated mice survived to Day 30. Pulmonary glutathione peroxidase, catalase, and superoxide dismutase activities were unaffected up to 6 days following 35 mg/kg BCNU, 85% oxygen, or both. Pulmonary glutathione reductase activity was unaffected by 85% oxygen alone, although hyperoxia extended the BCNU-induced inhibition of this enzyme to Day 6. BCNU, 35 mg/kg, had little effect on lung reduced glutathione (GSH) levels. A significant decrease was only measured on Day 4. Hyperoxia, either alone or with BCNU, had no effect on lung GSH content The total lung content of hydroxyproline, an index of fibrosis, was unchanged by BCNU-treatments either alone or in combination with oxygen. These data show that single BCNU doses of 35 mg/kg or more can increase the lethal effect of hyperoxia. The mechanism of this effect remains unclear since, while glutathione reductase was the only antioxidant enzymatic activity inhibited, GSH levels remained unchanged.