The effects of BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) and CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea) on glutathione reductase and other enzymes in mouse tissue

BCNU has been reported to cause a rapid, irreversible inhibition of human erythrocyte glutathione reductase (GR) at chemotherapeutic dosage, without affecting metabolic enzymes. This inhibition may mediate some of the therapeutic and toxic effects of BCNU. Thiol containing agents such as reduced glutathione can protect cells against BCNU and a change in glutathione concentrations could modify BCNU effectiveness. At doses of 50 mg/kg (LD-50) and 100 mg/kg, i.p., BCNU decreased the activity of GR in mouse kidney, liver, brain, and heart with a greater loss in those animals which died from drug administration. GR activity tended to recover but still remained below control at 96 hours. Erythrocyte GR activity was reduced only at the higher BCNU dose. CCNU (100 mg/kg, i.p.) did not affect GR activity. BCNU also decreased creatine kinase, malate dehydrogenase, and lactate dehydrogenase activities. The inhibition of GR in vitro occurred only after biochemical reduction of the enzyme with NADPH. The oxidation state of GR may determine its sensitivity to BCNU in the human erythrocyte but we were unable to demonstrate an unusually high sensitivity or a specific effect of BCNU on GR in mouse tissues.