The Chemopreventive Role of Ursodeoxycholic Acid in Colon Cancer Model : Suppressive Effects on Enhanced Group II Phospholipase A2 Expression

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We here report the possible suppressive mechanisms of ursodeoxycholic acid (UDCA) on azoxymethane (AOM) -induced colon cancer model rat. In relation to arachidonate metabolism, we focused on the regulation of group II phospholipase A_2 (PLA_2) expression after AOM treatment. (Materials and Methods) (1) F344 rats were fed standard diet containing 0.4% or 1% of UDCA.Total aberrant crypt counts along with enzymatic activity, protein mass, and steady-state mRAN levels of group II PLA_2 were determined at 2,4,6,12 weeks after exposure of AOM.(2) HepG2 cells incubated with 50microM UDCA were stimulated by IL-6 and TNF-alpha. The expression levels of group II PLA_2 protein and mRNA were determined. (Results) (1) Twelve weeks after AOM exposure, the total number of aberrant crypt foci in 0.4% UDCA-diet fed rats and 1% UDCA-diet fed rats was significantly decreased compared to the untreated animals. The mucosal concentration of PGE_2 and 6-keto-PGF1alpha were significantly lower in the UDCA-trested rats than untreated rats. In correlation with lowering, the enhanced activity, protien mass, and mRNA levels of group II PLA_2 were significantly attenuated in the UDCA-treated animals. (2) Pro-inflammatory cytokine-induced group II PLA_2 expression in HepG2 cells were suppressed by incubation with UDCA.(Conclusions) UDCA administration decreased the total number of aberrant crypt foci in AOM-treated colonic tissue in which the enhanced group II PLA_2 expression was significantly attenuated. This chemopreventive role of UDCA in colon carcinogenesis may lie in its modulation of the arachidonate metabolism in colonic mucosa. In addition, it is supposed that this suppressive effect may be caused from direct action of UDCA to inflammed cells.