The effect of lithocholic acid on proliferation and apoptosis during the early stages of colon carcinogenesis: differential effect on apoptosis in the presence of a colon carcinogen

Lithocholic acid (LCA) is implicated in human and experimental animal carci nogenesis. Its effect on apoptosis and proliferation of the colonic epithel ium was studied in a 1,2-dimethylhydrazine (DMH)-induced murine carcinogene sis model, Four groups of mice, control, LCA, DR;IH and DMH+LCA, were studi ed for 4 weeks, a period corresponding to early stages of carcinogenesis. A poptosis (AI) and proliferation (PT) indices in the colon were determined b y immunohistochemistry. LCA stimulated apoptosis [AI = 1.2 +/- 0.3% tall va lues are the mean +/- SEM) versus control 0.5 +/- 0.1%, P < 0.05], as did D MH (4.3 +/- 0.8%, P < 0.02). DMH increased apoptosis at the base of the cry pt nearly 50-fold, with no effect at the lumenal third, In mice receiving D R IH, LCA suppressed apoptosis almost completely (0.1 +/- 0.03%); this supp ression was complete at the lower two-thirds of the crypt (AI = 0) and 60% at the lumenal third. LCA increased proliferation (PI = 22.2 +/- 4.6% versu s 15.4 +/- 1% in controls), but this did not reach statistical significance . DMH increased proliferation (PI = 34.6 +/- 2.3%, P < 0.01), In mice recei ving DMH, proliferation (41 +/- 2.9%) was about two-thirds of the additive effect. LCA affected proliferation, mainly in the middle third of the crypt ; DMH's effect was similar in distribution, but more pronounced. In mice re ceiving DMH, LCA shifts proliferation upward, extending it to the lumenal t hird of the crypt, LCA's main cell kinetic effect in the colon is on apopto sis; this effect differs in normal (stimulation) and pre-malignant colon (n early complete suppression). LCA does not significantly stimulate prolifera tion in either normal or pre-malignant colon. The differential effect of LC A on apoptosis in the presence of a carcinogen partially explains its effec t as a promoter on colon carcinogenesis in animal models, and may have impo rtant implications for human carcinogenesis.