| Project/Area Number |
10671173
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Nagoya University |
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Principal Investigator |
KAMIYA Junichi Nagoya University, School of Medicine, Assistant Professor, 医学部, 講師 (70194975)
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| Co-Investigator(Kenkyū-buntansha) |
YUASA Norihiro School of Medicine, Research Associate, 医学部, 助手 (00303610)
NAGINO Masato School of Medicine, Assistant Professor, 医学部, 講師 (20237564)
NIMURA Yuji School of Medicine, Professor, 医学部, 教授 (80126888)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1998: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | Lithocholic acid / DNA polymerase / Tumor promoter / Colon carcinogenesis / bile acids / alkylating agents / Inhibition / Base-excision repair / DNAポリメラーゼ / DNA修復阻害 |
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| Research Abstract |
1. Seventeen kinds of bile acids were examined with respect to inhibition of enkaryotic DNA polymerase (pol) α, β, γ, δ, and ε in vitro. Only lithocolic acid (LCA) and its derivatives inhibited by LCA. The inhibition mode of pol β was the most sensitive to inhibition by LCA. The inhibition mode of pol β was non-competitive with DNA template-primer and was competitive with substrate with the Ki value of 10 μM. Chemical structures of C-7 and C-12 positions in the sterol skeleton were important for the inhibitory activity of LCA. With respect to inhibition of DNA replicative polymerases, LCA mildly inhibited pol α, while it did not inhibited pol δ. LCA weakly inhibited pol ε, that plays a role in the UV-induced nucleotide excision repair and DNA replication. LCA weakly inhibited pol γ, a mitchondrial DNA replicative polymerase.
2. In a human leukemic cell line (K562), to examine the effect of bile acids on cytotoxicities caused by DNA monomethylating agents or UV irradiation, bile acids were added after the treatment with methyl methanesulfonate or UV irradiation. LCA mildly enhanced cytotoxic effect of methyl methanesulfonate without promoting cytotoxity to pol β and the weak inhibition to pol ε of LCA in vitro.
LCA may suppress base-excision repair that is dependent on pol β, a repair pathway of DNA damages caused by monomethylating agents, via the pol β inhibition. The inhibition of base-excision repair by LCA could be correlated with its tumor promoting activity in colon cancer induced by alkylating agents.
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