Lithocholic Acid, a Putative Tumor Promoter, Inhibits Mammalian DNA Polymerase β

• Published in: Cancer science Vol. 89; no. 11; pp. 1154 - 1159
• Main Authors: Ogawa, Akio, Murate, Takashi, Suzuki, Motoshi, Nimura, Yuji, Yoshida, Shonen
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.1998; Japanese Cancer Association; John Wiley & Sons, Inc
• Subjects: Acids; Animals; Bile; Bile acids; Bile Acids and Salts - metabolism; Bile Acids and Salts - pharmacology; Biological and medical sciences; Carcinogenesis; Carcinogens - toxicity; Colon; Colon - drug effects; Colon - enzymology; Colon - pathology; Colon carcinogenesis; Deoxyribonucleic acid; DNA; DNA polymerase; DNA Polymerase beta - antagonists & inhibitors; DNA polymerase β; DNA repair; DNA-directed DNA polymerase; Epithelial cells; Epithelial Cells - drug effects; Gastroenterology. Liver. Pancreas. Abdomen; Hydroxylation; Inhibitor; Isoenzymes - antagonists & inhibitors; Kinetics; Linear Models; Lithocholic acid; Lithocholic Acid - toxicity; Medical sciences; Rats; Sodium; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumor promoter; Tumors; Animal model; Rat; Induction; Tumor promotor; Rodentia; Polymerization; Malignant tumor; Experimental study; Carcinogenesis; Colonic disease; Vertebrata; Mammalia; Enzymatic activity; Bile acid; Animal; DNA; Digestive diseases; Intestinal disease; Colon
• ISSN: 0910-5050; 1347-9032; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.1998.tb00510.x

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, η, 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.