Effect of ursodeoxycholic acid on azoxymethane-induced aberrant crypt foci formation in rat colon: in vitro potential role of intracellular Ca2+.
The studies were conducted to examine the precise nature of the suppressive effect of ursodeoxycholic acid (UDCA) on colonic aberrant crypt foci (ACF) formation. Fischer 344 rats were treated with a single dose of azoxymethane (AOM) (20 mg/kg, s.c.) and fed basal diet (MF) supplemented with UDCA (0.4%) during an initiation or a post-initiation stage. ACF were enumerated at the 2nd, 5th and 8th weeks after AOM administration (15-18 rats/group). The number of ACF in the UDCA treated group was decreased significantly in the initiation and post-initiation stages at the 2nd (P < 0.01, P < 0.0001) and 8th weeks (P < 0.001, P < 0.0001), respectively, compared with untreated controls. In the time-course experiments, the effect of continuous feeding of UDCA (0.4%) on ACF formation was evaluated. ACF number was decreased significantly (P < 0.005) until the 16th week. UDCA showed a significant dose-dependent suppression of ACF number from a range of 0.1-0.4% UDCA. To approach the subcellular mechanisms of the effect of bile acids, the intracellular free Ca2+ concentration ([Ca2+]i) of bile acid-treated rat colonic cancer cells (ACL-15) was examined. DCA and CDCA, which are promotive on ACF formation, induced a rapid increase in [Ca2+]i, while UDCA and CA, which are suppressive or non-effective on ACF formation, did not. These findings suggest that the promotive effect of bile acids may involve intracellular Ca2+ signaling.
Momen
Mohammed Abdul
MA
Second Department of Surgery, University Hospital, University of Tokushima School of Medicine, Tokushima, Japan.
Monden
Yasumasa
Y
Houchi
Hitoshi
H
Umemoto
Atsushi
A
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D001647:Bile Acids and Salts / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002273:Carcinogens / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D003106:Colon / Q000187:drug effects / Q000473:pathology*; D003110:Colonic Neoplasms / Q000473:pathology / Q000517:prevention & control; D004032:Diet; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007424:Intracellular Fluid / Q000378:metabolism*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D001647:Bile Acids and Salts; D002273:Carcinogens; D014580:Ursodeoxycholic Acid; D001397:Azoxymethane; D002118:Calcium