Journal Article

3-Amino-1, 4-dimethyl-5<i>H</i>-pyrido[4, 3-<i>b</i>]indole (Trp-P-1) inhibits the binding activity of T4 endonuclease V to UV-damaged DNA

Kayoko Shimoi, Rieko Miyamura, Toshio Mori, Takesi Todo, Eiko Ohtsuka, Keiji Wakabayashi and Naohide Kinae

in Carcinogenesis

Volume 17, issue 6, pages 1279-1283
Published in print June 1996 | ISSN: 0143-3334
Published online June 1996 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.6.1279
3-Amino-1, 4-dimethyl-5H-pyrido[4,
                        3-b]indole (Trp-P-1) inhibits the binding activity of T4
                    endonuclease V to UV-damaged DNA

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3-Amino-1, 4-dimethyl-5H-pyrido[4, 3-b]indole (Trp-P-1) is a mutagen/carcinogen derived from cooked foods which enhances the induction of mutations and chromosome aberrations by UV without microsomal activation. These co-mutagenic effects are considered to arise from inhibition of DNA excision repair at the incision step. However, the inhibition mechanism has not been clarified. in this study we show, using agarose gel electrophoresis, thatTrp-P-1 inhibits incision by T4 endonuclease V, which cleaves DNA at the site of cyclobutane dimers. Trp-P-1 also inhibitsthe binding of this enzyme to UV-damaged DNA in a gel shift assay. In addition, the results of DNA unwinding assay with topoisomerase I suggest that Trp-P-1 intercalates into DNA molecules. The known intercalators ethidium bromide and acriflavine demonstrate similar effects in these experiments. However, 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP), which showed no co-mutagenic effects in our previous study, does not demonstrate such effects. These resultssuggest that Trp-P-1 changes DNA conformation by intercalation, causing inhibition of binding of repair enzymes to UV-damaged DNA, and this in turn leads to inhibition of DNA excision repair and to co-mutagenic effects.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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