EFFECTS OF ENZYME-INDUCTION ON THE DISTRIBUTION OF THE FOOD CARCINOGEN 2-AMINO-3,8-DIMETHYL-IMIDAZO[4,5-F]-QUINOXALINE (MEIQX) IN AH-RECEPTOR-RESPONSIVE AND AH-RECEPTOR-NON-RESPONSIVE MICE

The distribution of the food carcinogen 2-amino-3,8-dimethyl-imidazo[4 ,5-f]quinoxaline (MeIQx) was studied in Ah-responsive-(C57BL/6J) and A h-non-responsive mice (DBA/2N). The time dependent organ distribution of radioactivity after C-14-MeIQx (10 mg/kg) administration in C57BL/6 J showed that al day 4 most of the radioactivity had been excreted and that the remaining radioactivity was found in liver, kidneys, lungs a nd spleen. C57BL/6J bound more radioactivity in the kidneys than the D BA/2N strain whereas approximately the same amount was left in the liv er and lungs in both strains 4 days after MeIQx exposure. Liver micros omes of the two strains had approximately the same ability to activate MeIQx in the Ames Salmonella assay. beta-Naphthoflavone treatment of the animals greatly increased microsomal activating capacity, but only in the C57BL/6J strain. Isosafrole treatment of the animals only slig htly increased the activating capacity, but particularly with microsom es from the DBA/2N strain, displacement of the putative inhibitory iso safrole metabolite greatly increased their activating capacity. In the whole animals pretreatment with beta-naphthoflavone, which induces P4 50IA only in the C57BL/6J strain, did not significantly change the amo unt of retained radioactivity in any of the strains. Isosafrole induce s only P450IA2, the major N-2-hydroxylating enzyme of heterocyclic ami nes, in both strains. Such pretreatment reduced the amount retained in the kidney of both strains whereas it reduced the retained amount of radioactivity in the liver with about 60% only in the Ah-non-responsiv e strain (DBA/2N). The effect of isosafrole did not persist when MeIQx was given three days after the last injection. The results indicate t hat induction by beta-naphthaflavone in the C57BL/6J mice increases P4 50IA dependent N-2-hydroxylation. The lack of change in MeIQx binding may be due to enhancement also of detoxification, but more likely, the rate limiting step is the ultimate esterification of the N-2-hydroxyl amine derivative. With isosafrole, which induces only P450IA2 in both strains, the results indicate that an isosafrole metabolic product inh ibits P450IA2 activity also in vivo. Treatment with phenethyl isothioc yanate which has been claimed to block the action of certain carcinoge ns, caused an increased binding of MeIQx in the liver and kidneys of C 57BL/6J mice.