Activation of the colon carcinogen 1,2-dimethylhydrazine in a rat colon cell-mediated mutagenesis assay.
Suspensions of rat colon epithelial cells metabolized the potent colon carcinogen, 1,2-[14C]dimethylhydrazine (DMH), into 14C-labeled, alkali-soluble volatile products, presumably CO2. The colon cell suspensions, however, were less effective than rat hepatocyte suspensions. In addition, we used a cell-mediated mutagenesis assay to test rat colon epithelial cells grown from tissue explants for their ability to metabolize DMH into products mutagenic for human P3 teratoma cells. Mutagenesis in the P3 cells was indicated by an acquired resistance to 6-thioguanine. Cocultivation of the colon cells with the P3 cells in the cell-mediated assay resulted in mutagenesis, whereas in the absence of the colon cells, no mutagenesis by DMH was observed. Similar results were obtained in a hepatocyte-mediated mutagenesis assay. Colon cells were also able to activate another carcinogen, benzo(a)pyrene, into products mutagenic for the P3 cells. Individual epithelial clonal populations isolated from the colon cultures grown from tissue explants, however, expressed different capacities to activate DMH and benzo(a)pyrene into mutagens, and a high degree of DMH activation by cells from a colon clone was not necessarily associated with a similar degree of benzo(a)pyrene activation. Our results indicate that the colon itself contains epithelial cell types capable of effectively converting DMH into mutagenic (and presumably carcinogenic) products without necessarily involving intermediary metabolism by hepatocytes as previously thought.
D019813:1,2-Dimethylhydrazine; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000139:chemically induced*; D004127:Dimethylhydrazines / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced; D008297:Male; D008763:Methylhydrazines / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D002273:Carcinogens; D004127:Dimethylhydrazines; D008763:Methylhydrazines; D009153:Mutagens; D001564:Benzo(a)pyrene; D019813:1,2-Dimethylhydrazine