Mechanism of 3-methylcholanthrene-induced inhibition of dimethylnitrosamine demethylase in rat liver.

Abstract

Summary Previous studies on the inhibitory action of pretreatment of rats with 3-methylcholanthrene (MC) and other polycyclic hydrocarbons on the hepatic dimethylnitrosamine demethylase were extended. Experiments to test the presence of an endogenous inhibitor or inactivator of the demethylase in the cytoplasm of liver pretreated with MC yielded negative results. Kinetic studies showed considerable decrease in the Vmax and no alteration in the Km of the demethylase following MC administration. This suggests that the decrease of activity is due to a reduction of the amount of enzyme in microsomal preparations from hydrocarbon-pretreated rats. Phenobarbital inhibits dimethylnitrosamine demethylation, although to a lesser extent than MC. Prolonged repeated treatment of sexually immature female rats with high doses of 17α-methyltestosterone evokes no change in demethylase activity. MC brings about the same inhibition in young adult males and females, and this inhibition is quantitatively similar to that observed in immature male rats. When the hydrocarbon is administered to rats along with actinomycin D or puromycin, the inhibitory effects on demethylation are additive. This appears to rule out the possibility that MC acts at the same target as these antibiotics. The totality of the available data suggests that MC (and other polycyclic hydrocarbons) possibly turns off the gene(s) coding for dimethylnitrosamine demethylase.