TISSUE DISTRIBUTION OF DNA-ADDUCTS OF 7H-DIBENZO[C,G]CARBAZOLE AND ITS DERIVATIVES IN MICE FOLLOWING TOPICAL APPLICATION

7H-Dibenzo[c,g] carbazole (DBC) is a potent liver and skin carcinogen following topical administration. The objective was to determine the p attern of DBC-DNA adducts produced in both target and nontarget tissue s when DBC and its metabolites were applied topically at carcinogenic doses. DBC phenolic derivatives 1-hydroxy-DBC, 2-hydroxy-DBC, 3-hydrox y-DBC, 4-hydroxy-DBC, 5-hydroxy-DBC, 6-hydroxy-DBC, 13-c-hydroxy-DBC, and N-methyl-DBC were applied dermally to Hsd:ICR (Br) mice. Tissues w ere harvested 24 h later, and DBC-DNA adduct levels were determined by P-32-postlabeling, The levels of DBC-DNA adducts were about 25 times greater in liver than in any other tissue. Total DBC-DNA adducts were seen in skin and lung at about equal levels, while adduct levels in ki dney and other tissues were no more than one fourth that of lung and s kin. Adduct 6 was the predominant adduct in liver, adducts 2 and 3 wer e formed preferentially in skin, and adduct 3 was formed preferentiall y in lung. 3-Hydroxy-DBC and 4-hydroxy-DBC produced higher levels of D NA adducts in skin, lung, and liver than did the parent compound or 2- hydroxy-DBC. DNA adducts were not seen in any tissue for the 1-, 5-, 6 -, or 13-c-hydroxy compounds. In addition, hepatic DNA adducts were no t seen when the nitrogen of DBC was methylated. In lung and skin, N-me thyl-DBC induced DNA adducts at levels comparable to DBC, although the adduct profile in these tissues was different from that of DBC itself . The data indicate that the 2, 3, and 4 phenolic metabolites of DBC a re involved in the activation pathway(s) of DBC, that specific DBC-DNA adducts are associated with specific target organs, and that the posi tion of the substituent on DBC rather than its chemical structure may be more important in DBC activation.