title: 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) sensitizes mammalian cells to UV radiation by causing the S-phase arrest, not by inhibiting the repair of DNA damage as observed in Escherichia coli.
abstract: 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is known to be a mutagen and carcinogen isolated from the charred parts of cooked foods. We found previously that Trp-P-1 enhanced UV-induced lethality and mutation frequency in Escherichia coli by inhibiting the repair of UV-induced DNA damage. In the present study, we investigated whether Trp-P-1 also potentiated UV-induced lethality by inhibiting the repair of UV-induced DNA damage in cultured mammalian cells. As a result, Trp-P-1 enhanced UV-induced lethality in a concentration-dependent manner in human and Chinese hamster cells. However, Trp-P-1 was unable to inhibit the repair of the two major photolesions (cyclobutane pyrimidine dimers and (6-4)photoproducts) from the genomic DNA, as determined using monoclonal antibodies specific for each type of lesion. On the other hand, Trp-P-1, with or without UV irradiation, efficiently suppressed DNA synthesis and arrested cells in S phase in concentration- and time-dependent manners, as measured by pulse-labelling with 3H-thymidine and flow cytometry. Thus, the present results suggest that Trp-P-1 potentiates UV-induced lethality in cultured mammalian cells by causing the S-phase arrest, not by inhibiting the repair of UV-induced DNA damage as observed in Escherichia coli.
authors.affiliation: Radioisotope Center, Nara Medical University, Japan. tmori@naramed-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Mori
authors.forename: A
authors.initials: A
authors.lastname: Nakagawa
authors.forename: N
authors.initials: N
authors.lastname: Kobayashi
authors.forename: M W
authors.initials: MW
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: K
authors.initials: K
authors.lastname: Shimoi
authors.forename: N
authors.initials: N
authors.lastname: Kinae
mesh_terms: D000818:Animals; D016466:CHO Cells; D002243:Carbolines / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000633:toxicity*; D016196:S Phase / Q000187:drug effects* / Q000528:radiation effects*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D002243:Carbolines; D011838:Radiation-Sensitizing Agents; D004247:DNA; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole