Marked differences between mutagenicity in Salmonella and tumour-initiating activities of dibenzo[a,e]fluoranthene proximate metabolites; initiation inhibiting activity of norharman.

Dibenzofluoranthene-12,13-dihydrodiol (DBF-12,13-DHD) is six times more mutagenic in Salmonella TA100 than dibenzofluoranthene-3,4-dihydrodiol (DBF-3,4-DHD). However, these two major dibenzo[a,e]fluoranthene (DBF) proximate metabolites, which are immediate precursors of the corresponding diolepoxides, showed on an equimolar basis nearly identical initiation activities on mouse skin; they induced three times more papillomas than the parent hydrocarbon. On the other hand the epithelioma initiation capacities, i.e. the number of papillomas progressing to malignant tumours, of DBF or the two dibenzofluoranthene dihydrodiols were equivalent. Norharman, a putative vicinal diolepoxidation inhibitor in DBF metabolism when administered topically together with the initiation dose (100 nmol), strongly inhibited the induction of tumours by DBF-3,4-DHD and DBF. The relationship between in vitro mutagenic activity in Salmonella and the carcinogenicity of DBF metabolites in mice appears to be qualitative rather than quantitative.