Genes and Environment
Online ISSN : 1880-7062
Print ISSN : 1880-7046
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29 巻 , 1 号
選択された号の論文の4件中1~4を表示しています
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REVIEW
  • Satoko Ishikawa, Masataka Mochizuki
    29 巻 (2007) 1 号 p. 1-10
    公開日: 2007/03/09
    ジャーナル フリー
    DNA alkylation and cross-linking are classical mechanisms underlying the activity of cancer chemotherapeutic agents such as procarbazine and mitomycin C, which are currently used in the clinic. Chloroethyl N-nitrosoureas is one group of anticancer cross-linking agents, and exert their biological activities by formation of DNA cross-links. Because anticancer chloroethyl N-nitrosoureas shows toxic side-effects due to protein carbamoylation, many efforts have been exercised to reduce unwanted side-effects by design of new drugs with low carbamoylating activity. N-Nitrosamines, another category of N-nitroso compounds, alkylate cellular nucleophiles in vivo, and might induce gene mutation and lead to carcinogenesis by DNA alkylation. Its active form is released after elimination of aldehyde; i.e. N-nitrosamines do not carbamoylate proteins. We have an interest in structure modification of alkylating nitrosamines as useful candidates for anticancer lead compounds. Three N-nitroso-N-(acetoxymethyl)-ω-chloroalkylamines, chloroethyl, chloropropyl and chlorobutylamines have been synthesized and their chemical and biological properties were evaluated. The chloropropyl nitrosamine showed mutagenicity in Salmonella typhimurium TA92 that is positively responsive to DNA cross-linker, and also showed interstrand cross-linking activity towards plasmid DNA assayed by agarose gel electrophoresis. Then three-ring aromatic moieties were introduced into the structure of chloropropyl nitrosamine to potentiate its binding affinity to DNA molecules. Although three aromatic analogs intercalated to double-stranded DNA, only acridine analog had DNA cross-linking activity. In TA92 strain, the acridine analog showed the highest mutagenicity among all nine N-nitroso compounds used in this study. These results suggest that the aromatic ring moiety confers DNA-intercalating ability to the cross-linkable chloropropyl nitrosamine; the acridine analog that forms DNA cross-links efficiently might be a potential new anticancer lead compound. To assess the application of cross-linkable nitrosamines as new anticancer agents, further investigations such as that on DNA adducts or on their activity towards cancer cells are required.
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REGULAR ARTICLES
  • Masashi Sekimoto, Hiroto Kawamagari, Saki Nakatani, Kiyomitsu Nemoto, ...
    29 巻 (2007) 1 号 p. 11-16
    公開日: 2007/03/09
    ジャーナル フリー
    To establish a human hepatic cell line for a convenient reporter gene assay of arylhydrocarbon receptor (AhR) activators, the chimera plasmid containing xenobiotic responsible element (XRE), minimal SV40 promoter, and luciferase reporter gene and the expression vector pRC/CMV containing a neomycin-resistant gene were co-transfected into a human hepatoma cell line, HepG2. Then, antibiotic (G418)-resistant HepG2 cells were selected and cloned. A cell clone, HepG2-A10, showed the highest responsibility to 3-methylcholanthrene (MC)-mediated induction of luciferase among the clones obtained. Expression levels of luciferase activity in HepG2-A10 cells were increased in a dose- and time-dependent manner by treatment with either MC, an AhR-ligand type activator, or omeprazole (OME), a non-AhR ligand type activator. In addition, expression levels of cytochrome P4501A subfamily genes (CYP1A1 and CYP1A2) were also increased in a dose- and time-dependent manner by treatment with MC. The present findings demonstrate that a newly established human HepG2-A10 is a useful cell line for a convenient reporter gene assay of AhR activators.
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  • Yoshimi Nishio, Yumiko Nakano, Yuya Deguchi, Hiroaki Terato, Hiroshi I ...
    29 巻 (2007) 1 号 p. 17-22
    公開日: 2007/03/09
    ジャーナル フリー
    We investigated whether or not social stress (isolation, 1 mouse per cage) increases oxidative DNA damage in mouse peripheral blood cells. Male BALB/c mice (4 weeks old) were housed 5 per cage for 10 days. After acclimatization, mice were exposed to isolation stress for 7 and 30 days. Control mice were housed 5 per cage. Serum levels of corticosterone, which is a well known stress marker, and antioxidant compounds, ascorbic acid and α-tocopherol, were determined by liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) and ESACoul Array analysis, respectively. Single cell gel electrophoresis (comet assay) using formamidopyrimidine DNA glycosylase (FPG) was done to determine oxidative DNA damage in mouse peripheral blood cells. The significant increases of plasma level of corticosterone were observed in mice exposed to isolation stress for 7 days and 30 days. Although no significant differences in plasma concentration of ascorbic acid and α-tocopherol were observed between the control mice and the isolated mice, oxidative DNA damage was induced in the isolated mice for 7 days and 30 days. These results suggest that social stress, isolation, causes mild oxidation in mice.
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SHORT COMMUNICATION
  • Katsuhito Kino, Hiroshi Miyazawa, Hiroshi Sugiyama
    29 巻 (2007) 1 号 p. 23-28
    公開日: 2007/03/09
    ジャーナル フリー
    Photosensitized oxidation of guanine provides various oxidation products, including 8-oxoguanine (8-oxoG) and imidazolone. Riboflavin (vitamin B2) is known as an effective photosensitizer for oxidation of guanine. Here, we show the user-friendly synthesis and photoreaction of a flavin-linked oligonucleotide; the practical synthesis of a hydroxyethyl-flavin (2) from commercially available riboflavin; and the preparation of a flavin-linked oligonucleotide using the phosphoramidite of 2. To demonstrate the usefulness of this method, the flavin-linked oligomer flavin-5′-d(T6CCT6)-3′ was synthesized. Flavin-5′-d(T6CCT6)-3′ and its complementary 5′-d(A6G8-oxoGA6)-3′ were irradiated under UV light (366 nm) at neutral pH. Enzymatic digestion of the irradiated mixture with P1 nuclease and alkaline phosphatase indicated that the 8-oxoG residue was oxidized to imidazolone. These results demonstrate that 8-oxoG is effectively oxidized to imidazolone by photosensitization of the terminal flavin via a hole-transfer mechanism, and imidazolone is formed by one-electron oxidation of 8-oxoG at neutral pH.
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