Age course and inducibility of dimethylnitrosamine N-demethylation in rat liver

Dimethylnitrosamine (DMN)-N-demethylation by 10,000 x g liver supernatant follows a typical Michaelis-Menten kinetics with one apparent Km (4.0 . 10(-4) M) and V max (0.460 nmole/mg . min) of 30-day-old male rats. The investigation of hepatic DMN-N-demethylation in dependence on age reveals maximum activities in 30- to 60-day-old male rats. The demethylating enzyme activity is inducible by phenobarbital (PB), not by 3-methylcholanthrene (3-MC). Pretreatment of animals with PB plus 3-MC resulted in reduced inducibility compared with PB-pretreatment alone. Probably this is not due to an inhibition of PB-induction by 3-MC, but effected by PB residues in the liver tissue and in the incubation mixture. The elimination rate of PB in young rats seems to be retarded if high doses of the inducers PB and 3-MC are administered simultaneously. Additionally changes in inducible cytochrome P-450 subspecies have to be considered.