Norharman and ellipticine: a comparison of their albilities to interact with DNA in vitro.
The anti-tumor agent ellipticine has been compared in vitro with the bacterial co-mutagen norharman, a compound which it resembles superfically in chemical structure. Ellipticine was shown to stabilize the structure of double stranded calf-thymus DNA, to induce mutations in strain TA153 of Salmonella tryhimurium and to cause BHK cells to transform. Further, the major absorbance in its visible spectrum underwent a red shift of approximately 40 nm in the presence of native DNA. It is concluded that ellipticine intercalates with dna, and from this, that its action as an anti-tumor agent may, as has been previously suggested, be dependent upon this property. In contrast, norharman, a chemical suspected initially of being an intercalating agent, failed to stabilize the structure of DNA, was non-mutagenic to the same strain of S. typhimurium and was inactive as cell-transforming agent. In addition, its visible spectrum was not affected by the presence of DNA. The last observation is contrary to the conclusion of other workers, and an explanation of this difference is given. It is concluded that norharman is not capable of intercalating with DNA, and consequently, its mode of action as a co-mutagen is probably dependent upon its ability to inhibit certain mixed-function oxidase enzymes present in the liver activation system employed with in vitro mutagenicity assays.