Inhibitory effects of ursodeoxycholic acid on N-methylnitrosourea-induced colon carcinogenesis and colonic mucosal telomerase activity in F344 rats.
Bile acids are known to promote colon carcinogenesis. However, one study showed that ursodeoxychlic acid (UDCA) prevented azoxymethane-induced rat colon tumorigenesis. The aim of the present study with 3 sets of experiments was to explore the inhibitory effect of UDCA supplemented in the diet on colon carcinogenesis induced by the intrarectal administration of N-methylnitrosourea (MNU) in F344 rats. In experiment I, 5 rats per group were fed a diet supplemented with 0% (control), 0.4%, 0.08% or 0.016% UDCA or chenodeoxycholic acid (CDCA) for 5 weeks after receiving 3 intrarectal doses of 4 mg MNU in week 1. The formation of colonic aberrant crypt foci (ACFs, preneoplastic lesions) at week 6 showed a 24% and 23% reduction in the 0.4% and 0.08% UDCA groups, respectively, as compared to the control group, while it increased for the 0.4% and 0.08% CDCA groups, and was unaffected in the 0.016% UDCA and CDCA groups. In experiment II based on the results of experiment I, all rats received an intrarectal dose of 2 mg MNU 3 times a week for 3 weeks, and then were administered with 0%, 0.4% or 0.08% UDCA for 27 weeks. At week 30, the incidence of colon tumors in the UDCA groups was significantly lower than that in the control group: 20/50 (40%) and 9/25 (36%) vs. 17/25 (68%). The number of large-sized ACFs with 4 or more ACs showed a 47% and 59% reduction in the normal-appearing mucosa in the UDCA groups as compared to the control group, while the number of small-sized ACFs with 1-3 ACs was similar in all groups. The normal-appearing mucosa showed a noticeable level of telomerase activity (semiquantitative PCR-based TRAP assay) in the control group, and significantly reduced levels in the UDCA groups compared to the control group: 19.8 and 32.7 vs. 71.0 TPG unit in mean value. The colon tumors showed a high level of enzyme activity in both the control and UDCA groups. In experiment III, 6 rats per group were fed a diet supplemented with 0%, or 0.4% UDCA or CDCA for 5 weeks after receiving 3 intrarectal doses of 4 mg MNU in week 1. Two control groups did not receive any treatment with MNU and bile acids. The MNU-treated groups showed significantly elevated levels of colonic mucosal telomerase activity at week 6 as compared to the control group (6.5 TPG unit in mean value). It was noted that both UDCA and CDCA administration reduced the enzyme activity as compared to the group with MNU treatment alone: 24.7 and 25.2 vs. 40.1 TPG unit in mean value. Thus, the present study suggested that orally administered UDCA inhibited the growth of ACFs and the development of carcinomas in the colon of rats treated with MNU. Also, UDCA may suppress MNU-induced telomerase activation in normal-appearing but ACF-containing colon mucosa, and its mechanism appears to be different from that responsible for the anti-tumor promoting action of UDCA.
Narisawa
T
T
Akita University College of Allied Medical Sciences, Hondo, Japan.
Fukaura
Y
Y
Terada
K
K
Sekiguchi
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000037:antagonists & inhibitors*; D003106:Colon / Q000201:enzymology; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000201:enzymology*; D008770:Methylnitrosourea; D051381:Rats; D011916:Rats, Inbred F344; D019098:Telomerase / Q000037:antagonists & inhibitors*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002273:Carcinogens; D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D008770:Methylnitrosourea; D014580:Ursodeoxycholic Acid; D019098:Telomerase