Enhanced oxygen toxicity following treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea.
The anticancer drug 1,3-bis(2-chloroethyl)-1-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-treated 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.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D002330:Carmustine / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D007928:Lethal Dose 50; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D010100:Oxygen / Q000633:toxicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced
D005980:Glutathione Reductase; D005978:Glutathione; D010100:Oxygen; D002330:Carmustine