Interaction of the oncolytic drug, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with the mixed-function oxidase system in rats

Abstract

Effects of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) on the hepatic mixed-function oxidase system in male rats were studied both in vivo and in vitro. A single dose of CCNU (40 mg/kg) caused a significant reduction in hepatic mixed-function oxidase activities within 3 days after administration. The depression was prolonged for cytochrome P-450, total haem and the metabolism of several type I substrates lasting up to 10 weeks after a single dose. By contrast, aniline hydroxylase, cytochrome b 5 and NADPH-cytochrome c reductase activities returned to near control levels after week two. Microsomal enzymes in the kidneys of treated animals however, were unaltered. Serum glutamic pyruvic and glutamic oxaloacetic transaminase and bilirubin levels, indicators of hepatotoxicity, were greatly elevated 3 days after CCNU treatment. These parameters fell rapidly but were still above control levels to the end of the 10-week study. When added in vitro, CCNU reduced apparent cytochrome P-450 content and the metabolism of type I substrates in microsomes from untreated, phenobarbital (PB) and 3-methylcholanthrene (3-MC)-pretreated rats. Total haem and NADPH-cytochrome c reductase were not affected whereas aniline hydroxylase activity was activated. CCNU interacted with hepatic microsomes to produce a type I difference spectrum.