Investigations into the metabolism and mode of action of the colon carcinogens 1,2-dimethylhydrazine and azoxymethane

Abstract

Colon cancer can be induced reliably in rodents with 1,2-dimethylhydrazine and azoxymethane (AOM). Our studies deal with the mode of action of these compounds and their organotropism. A partial summary of our previous work on the metabolism of 1,2-dimethylhydrazine and its inhibition by disulfiram, carbon disulfide and other thiono-sulfur compounds is presented. On-going studies with AOM-¹⁴C indicate that in male F-344 rats, this carcinogen is rapidly metabolized to ¹⁴CO₂ (37%,48 hours) and to methylazoxymethanol-¹⁴C (MAM) (0.6-1%), which, along with other metabolites, appears in the urine. Pretreatment of rats with phenobarbital or chrysene increased exhaled ¹⁴CO₂ to 53% and 65%, respectively. Pretreatment with disulfiram or CS₂ causes a complete, although transient, inhibition of exhaled ¹⁴CO₂, decreases urinary MAM, and increases significantly the levels of unmetabolized AOM in the exhaled air and in urine. Thus, phenobarbital and chrysene appear to stimulate, while disulfiram and CS₂ appear to inhibit, the metabolism of AOM. In vitro hydroxylation of AOM to MAM was demonstrated with rat liver homogenates and microsomal fractions. A hypothetical scheme for the endogenous formation of AOM is presented.