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 (Plt0.01, Plt0.0001) and 8th weeks (Plt0.001, Plt0.0001),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 (Plt0.005) until the 16thweek.UDCAshowed 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.