The potent colon carcinogen, 1,2-dimethylhydrazine induces mutations primarily in the colon

Abstract

1,2-Dimethylhydrazine (DMH) is a potent colon carcinogen that is commonly used as an initiator in studies of the effects of diet on colon cancer. Previous studies have shown that although this compound produces multiple tumors in the colons in most individuals of every species tested, it is, at best, marginally mutagenic in the bone marrow (micronuclei) and small intestine (Dlb-1 mutations). Here we report its mutagenicity in the primary target tissue, the colonic epithelium, by means of the Muta™Mouse cII assay, an assay for intragenic mutations in a lambda shuttle vector that is integrated into the genome of these mice. Animals were treated with 0, 10, 20, or 30 mg/ml of DMH, either as a single injection or as multiple weekly injections, and mutations were measured in both the small intestine and colon. In the small intestine, there was an increase in mutant frequency following a single injection of DMH, but this was significant only at 30 mg/kg [induced mutant frequency (MF) = 18 × 10 −5 mutants/plaque]. In the colon, following a single treatment of DMH, there was a significant increase in mutant frequency at doses of 20 and 30 mg/kg (induced MF = 17 × 10 −5 and 23 × 10 −5 mutants/plaque, respectively). Following ten injections of 20 mg/kg of DMH, there was a greater than ten-fold increase in mutations in the colon (MF = 275 × 10 −5 mutants/plaque) than the small intestine (MF = 25 × 10 −5 mutants/plaque). These results show that DMH, under the conditions typically used for dietary studies, induces large numbers of mutations in the tissue in which it induces most cancers.