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 (VOL 20, PG 243, 1996)

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 ib 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 and that th ese effects are mediated by changes in the expression of the protoonco genes c-Fos and c-Jun, which are known to regulate proliferation and d ifferentiation. Methods: Twenty-five adult Sprague-Dawley rats underwe nt colonic isolation and 24-hour intraluminal instillation of 10 mmol/ L sodium chloride, 10 mmol/L sodium butyrate, or 10 mmol/L sodium deox ycholate. Proliferation of the whole crypt and five crypt compartments from base to surface was assessed by proliferating cell nuclear antig en immunohistochemistry. The phi h value, an index of ''premalignant'' hyperproliferation, was calculated as the ratio of labeled cells in t he two surface compartments divided by the labeled cells in the entire crypt. Expression of c-Fos and c-Jun was evaluated by Western blot. R esults: Crypt surface proliferation and the phi h value were significa ntly decreased by butyrate and increased by deoxycholate. Butyrate inc reased colonic expression of c-Jun, whereas deoxycholate significantly induced c-Fas. Conclusions: The in vivo effects on surface proliferat ion are consistent with a potential protective role for butyrate and a promotive role for deoxycholate in colon carcinogenesis. The concurre ntly observed effects on colonic c-Jun and c-Fos expression represent a novel finding and suggest that direct or indirect modulation of prot ooncogene expression may be the mechanism by which these dietary bypro ducts regulate proliferation in vivo.