Metabolites of two structurally related chemical carcinogens, benzo[a]pyrene and 1-nitropyrene, were compared for their ability to cause cytotoxicity and induce mutations in normally repairing or nucleotide excision repair-deficient diploid human fibroblasts; for their ability to induce mutations in a defined gene sequence, supF, when a plasmid containing adducts formed by these carcinogens replicates in human 293 cells; and for their ability to induce homologous recombination between

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... genes in mouse L cells. Both of the metabolites tested, i.e., (± )-73,8a-dihydroxy-9a,1Oa, epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and 1-nitrosopyrene (1-NOP), form adducts on guanine. BPDE binds principally at the N2 position of guanine; 1-NOP binds to guanine at the C8 position. Results of the studies in diploid human cells indicated that when compared on the basis of equal numbers of DNA adducts, BPDE is more effective than 1-NOP in inducing mutations in DNA repair-proficient cells, but when compared in repair-deficient xeroderma pigmentosum human cells that do not remove such adducts from their DNA, the frequency of mutants induced per adduct is equal. These results suggest that during the time available for repair of potentially mutagenic lesions, repair-proficient human cells excise 1-NOP adducts more rapidly than they excise BPDE adducts. Molecular analysis. of the specific kinds of mutations induced when a plasmid containing BPDE residues was allowed to replicate in human cells showed that BPDE induces mainly base substitution mutations, predominantly G:C to T:A transversions. Preliminary results with 1-NOPtreated plasmids in that system indicate that 1-NOP is not as mutagenic as BPDE when the two carcinogens are compared on the basis of equal initial numbers of adducts per plasmid. Just as was the case for mutation induction in the genome of diploid human fibroblasts discussed above, the difference in mutagenicity per adduct may reflect a difference in excision repair rate by the human cell line 293. This question is under investigation. In addition, preliminary results of a study comparing 1-NOP with BPDE for ability to induce homologous recombination in mouse L cells indicate that BPDE is more effective than 1-NOP.