IN-VIVO CRYPT SURFACE HYPERPROLIFERATION IS DECREASED BY BUTYRATE ANDINCREASED BY DEOXYCHOLATE IN NORMAL RAT COLON - ASSOCIATED IN-VIVO EFFECTS ON C-FOS AND C-JUN EXPRESSION

Background: Studies on colon carcinogenesis suggest that the short-cha in fatty acid butyrate may be protective, whereas the secondary bile a cid deoxycholate may promote tumor development. Crypt surface hyperpro liferation is regarded as a biomarker of colon cancer risk and can be modulated in vitro by the differentiation inducer butyrate and the tum or promoter deoxycholate. We hypothesized that butyrate decreases and deoxycholate increases crypt surface proliferation in vivo acid that t hese effects are mediated by changes in the expression of the protoonc ogenes c-Fos and c-Jun, which are known to regulate proliferation and differentiation. Methods: Twenty-five adult Sprague-Dawley rats underw ent colonic isolation and 24-hour intraluminal instillation of 10 mmol /L sodium chloride, 10 mmol/L sodium butyrate, or 10 mmol/L sodium deo xycholate. Proliferation of the whole crypt and five crypt compartment s from base to surface was assessed by proliferating cell nuclear anti gen immunohistochemistry. The phi h value, an index of ''premalignant' ' hyperproliferation, was calculated as the ratio of labeled cells in the two surface compartments divided by the labeled cells in the entir e crypt. Expression of c-Fos and c-Jun was evaluated by Western blot. Results: Crypt surface proliferation and the phi h value were signific antly decreased by butyrate and increased by deoxycholate. Butyrate in creased colonic expression of c-Jun, whereas deoxycholate significantl y induced c-Fos. Conclusions: The in vivo effects on surface prolifera tion are consistent with a potential tumor-promoting role for butyrate and a promotive role for deoxycholate in colon carcinogenesis. The co ncurrently observed effects on colonic c-Jun and E-FOS expression repr esent a novel finding and suggest that direct or indirect modulation o f protooncogene expression may be the mechanism by which these dietary byproducts regulate proliferation in vivo.