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Investigations into the metabolism and mode of action of the colon carcinogens 1,2‐dimethylhydrazine and azoxymethane
Author(s) -
Fiala Emerich S.
Publication year - 1977
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(197711)40:5+<2436::aid-cncr2820400908>3.0.co;2-u
Subject(s) - disulfiram , azoxymethane , carcinogen , dimethylhydrazine , phenobarbital , urine , metabolism , aberrant crypt foci , pharmacology , chemistry , microsome , mode of action , endocrinology , biochemistry , medicine , colorectal cancer , in vitro , cancer , colonic disease
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‐ 14 C indicate that in male F‐344 rats, this carcinogen is rapidly metabolized to 14 CO 2 (37%,48 hours) and to methylazoxymethanol‐ 14 C (MAM) (0.6‐1%), which, along with other metabolites, appears in the urine. Pretreatment of rats with phenobarbital or chrysene increased exhaled 14 CO 2 to 53% and 65%, respectively. Pretreatment with disulfiram or CS 2 causes a complete, although transient, inhibition of exhaled 14 CO 2 , 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 CS 2 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.