EFFECTS OF PRETREATMENT WITH 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN ON THE CAPACITY OF HEPATIC AND EXTRA-HEPATIC MOUSE-TISSUES TO CONVERT PROCARCINOGENS TO MUTAGENS FOR SALMONELLA-TYPHIMURIUM AUXOTROPHS

Using the conventional Ames test, the conversion of three procarcinogens, 7,12-dimethylbenz(a)anthracene (DMBA), benzo(a)pyrene (BaP), and N-2-fluorenylacetamide (FAA) to intermediary metabolites mutagenic to Salmonella typhimurium tester strains TA-98, TA-100, but not TA-1538 was much more efficient in hepatic S-9 fractions prepared from TCDD-pretreated mice than in analogous fractions from untreated mice. In general, renal and pulmonary S-9 fractions from TCDD-pretreated mice also generated more back mutations than the corresponding controls however, statistical significance could not be demonstrated in every case. Exceptions were with DMBA, for which pulmonary S-9 fractions of TCDD-pretreated mice produced fewer mutations than corresponding fractions from control animals and with FAA, for which renal S-9 fractions of pretreated mice produced approximately the same numbers of mutations as fractions from control animals. Quantitation of the generation of metabolites cytotoxic to bacteria grown on nutrient agar revealed that TCDD pretreatment resulted in increases in the capacity of S-9 fractions from mouse hepatic tissue to generate cytotoxic metabolites from BaP and FAA but not from DMBA. The kidney was more responsive than the liver or lung to monooxygenase induction by the dioxin with BaP or DMBA as substrates but analyses of metabolite profiles with hplc indicated that TCDD pretreatment appeared to produce no qualitative differences in metabolites generated in the tissues studied. Differences of ratios of metabolites were noted with respect to DMBA metabolites cochromatographing with 7-hydroxymethyl-12-methylbenz(a) anthracene and trans-8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz(a)anthracene. Pretreatment of mice with TCDD produced 2- to 10-fold increases in the amounts of these two metabolites in comparison with slight to moderate increases in quantities of most other metabolites and a decrease in those eluting with 12-hydroxymethyl-7-methylbenz(a)anthracene. The effect was particularly prominent in the kidney. In general, the data indicated an overall positive correlation between the activity of tissue monooxygenases and capacity of the same tissues to metabolically convert procarcinogens to mutagens in the Ames system. © 1979.