TY - JOUR
T1 - Lithocholic acid, a putative tumor promoter, inhibits mammalian DNA polymerase β
AU - Ogawa, Akio
AU - Murate, Takashi
AU - Suzuki, Motoshi
AU - Nimura, Yuji
AU - Yoshida, Shonen
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 1998
Y1 - 1998
N2 - Lithocholic acid (LCA), one of the major components in secondary bile acids, promotes carcinogenesis in rat colon epithelial cells induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which methylates DNA. Base-excision repair of DNA lesions caused by the DNA methylating agents requires DNA polymerase β (pol β). In the present study, we examined 17 kinds of bile acids with respect to inhibition of mammalian DNA polymerases in vitro. Among them, only LCA and its derivatives inhibited DNA polymerases, while other bile acids were not inhibitory. Among eukaryotic DNA polymerases α, β, δ, ε, and γ, pol β was the most sensitive to inhibition by LCA. The inhibition mode of pol β was non-competitive with respect to the DNA template-primer and was competitive with the substrate, dTTP, with the Ki value of 10 μM. Chemical structures at the C-7 and C-12 positions in the sterol skeleton are important for the inhibitory activity of LCA. This inhibition could contribute to the tumor-promoting activity of LCA.
AB - Lithocholic acid (LCA), one of the major components in secondary bile acids, promotes carcinogenesis in rat colon epithelial cells induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which methylates DNA. Base-excision repair of DNA lesions caused by the DNA methylating agents requires DNA polymerase β (pol β). In the present study, we examined 17 kinds of bile acids with respect to inhibition of mammalian DNA polymerases in vitro. Among them, only LCA and its derivatives inhibited DNA polymerases, while other bile acids were not inhibitory. Among eukaryotic DNA polymerases α, β, δ, ε, and γ, pol β was the most sensitive to inhibition by LCA. The inhibition mode of pol β was non-competitive with respect to the DNA template-primer and was competitive with the substrate, dTTP, with the Ki value of 10 μM. Chemical structures at the C-7 and C-12 positions in the sterol skeleton are important for the inhibitory activity of LCA. This inhibition could contribute to the tumor-promoting activity of LCA.
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U2 - 10.1111/j.1349-7006.1998.tb00510.x
DO - 10.1111/j.1349-7006.1998.tb00510.x
M3 - Article
C2 - 9914784
AN - SCOPUS:0032440708
VL - 89
SP - 1154
EP - 1159
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 11
ER -