Effect of modifiers of the cytochrome P-450-dependent enzyme system of the liver on the metabolic pathways of diethylnitrosamine activation and inactivation

Pretreatment of Wistar male rats with antioxidants prevented the toxic effect of diethylnitrosamine (DENA) at LD50. Six-fold acceleration of DENA excretion and significant increase of maximum plasma concentration of a DENA metabolite nitrite were, also observed after antioxidants treatment. Liver microsomal metabolism of DNA was altered by pretreatment with another antioxidant--butylhydroxytoluene, which stimulated selectively denitrosation and inhibited dealkylation of DENA in the microsomal cytochrome P-450-dependent enzyme system. Moreover, butylhydroxytoluene treatment diminished he ability of microsomes to activate DENA to mutagenic intermediates identified in Ames' test. It was suggested that the protective effect of antioxidants against DENA toxicity may be due to the acceleration of its metabolic inactivation and the inhibition of its activation in liver cytochrome P-450-dependent systems.