Effects of bile acids on carcinogen-exposed rat colon in organ culture and as subsequent long-term transplants

Abstract

Rat (F344) colon fragments in organ culture were exposed for 4 to 6 hours to carcinogens and then for 4 days to deoxycholic acid or fecal extracts containing a mixture of in vivo-produced bile acids from animals fed low- or high-fat diets. Following exposures during culture, the fragments were transplanted into the mammary fat pads of syngeneic rats. The transplanted fragments survived for at least 1 year with preservation of crypt architecture and with continued DNA and mucin synthesis. Exposure in culture to N-methyl-N'-nitro-N-nitrosoguanidine (CAS: 70-25-7) or N-methyl-N-nitrosourea (CAS: 684-93-5) resulted in hypercellularity, hyperplasia, and cellular atypia in the transplants; but, in contrast to transplants from colon adenocarcinomas, no tumors formed. Exposure in culture to deoxycholic acid subsequent to N-methyl-N-nitrosourea or N-methyl-N'-nitro-N-nitrosoguanidine resulted in greater cellular abnormalities in transplants. Exposure after N-methyl-N-nitrosourea to fecal extracts from rats on a high-fat diet also enhanced the pathologic changes, whereas similar extracts from rats on a low-fat diet did not alter the pathology resulting from N-methyl-N-nitrosourea or N-methyl-N'-nitro-N-nitrosoguanidine exposures. It is concluded that bile acids, including those formed in vivo, facilitate the expression of carcinogen-induced abnormalities in the colon mucosa.