Apparent stimulation of dibenzo[a,e]fluoranthene in vitro metabolism in the presence of norharman.

The effects of norharman (NH) on the metabolism of dibenzo[a,e]-fluoranthene (DBF) and on its fixation on DNA, RNA and proteins have been studied in vitro by incubation with S-9 and microsomes from rats and mice. NH causes a decrease of the activity of microsome monooxygenases proportionally to its concentration but has no effect on the activity of NADPH P-450 reductase nor on that of epoxide hydrolase. Paradoxically, the amount of DBF hydrophobic metabolites and especially that of diols and phenols, increases in the incubation mixture in the presence of NH; this increase is independent of the presence of conjugation enzymes of cytosol. NH does not modify the covalent binding of DBF on the microsome RNA, conversely it decreases the binding of DBF on the DNA and on the proteins of the incubation mixture. This could partly explain the increase of DBF diols and phenols by an accumulative effect. Two higher homologs of NH: benzo[g]-beta carboline and benzo[i]-beta carboline, tested under the same conditions, proved inhibitory.