Effects of enzyme induction on the distribution of the food carcinogen 2-amino-3,8-dimethyl-imidazo[4,5-ss]-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-ss]quinoxaline (MeIQx) was studied in Ah-responsive-(C57BL/6J) and Ah-non-responsive mice (DBA/2N). The time dependent organ distribution of radioactivity after 14C-MeIQx (10 mg/kg) administration in C57BL/6J showed that at day 4 most of the radioactivity had been excreted and that the remaining radioactivity was found in liver, kidneys, lungs and spleen. C57BL/6J bound more radioactivity in the kidneys than the DBA/2N strain whereas approximately the same amount was left in the liver and lungs in both strains 4 days after MeIQx exposure. Liver microsomes 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 slightly increased the activating capacity, but particularly with microsomes from the DBA/2N strain, displacement of the putative inhibitory isosafrole metabolite greatly increased their activating capacity. In the whole animals pretreatment with beta-naphthoflavone, which induces P450IA only in the C57BL/6J strain, did not significantly change the amount of retained radioactivity in any of the strains. Isosafrole induces only P450IA2, the major N2-hydroxylating enzyme of heterocyclic amines, 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-responsive strain (DBA/2N). The effect of isosafrole did not persist when MeIQx was given three days after the last injection.(ABSTRACT TRUNCATED AT 250 WORDS)
Graduate Research Laboratory, Stabekk College, Bekkestua, Norway.
R
R
Vikse
K
K
Ingebrigtsen
L
L
Klungsøyr
J
J
Alexander
D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D004790:Enzyme Induction; D006900:Hydroxylation; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011810:Quinoxalines / Q000493:pharmacokinetics* / Q000633:toxicity; D012451:Safrole / Q000494:pharmacology; D013045:Species Specificity; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution
D002273:Carcinogens; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D012451:Safrole; C015959:isosafrole