Colon carcinogens: Their metabolism and mode of action

Abstract

Colon cancer in man almost certainly is induced by environmental factors, probably consumed with food. Except for one breed of hamsters, colon cancer is infrequent in laboratory or domestic animals. Reliable induction of colon cancer can be achieved with 2 broad classes of chemicals: 1. derivatives of 3‐methyl‐4‐aminobiphenyl, and 2. derivatives of 1, 2‐dimethylhydrazine, including the plant product cycasin. Sometimes an unknown ingredient of bracken fern causes cecal or colonic cancers. The metabolism of 4‐aminobiphenyl derivatives involves, among other steps, N‐hydroxylation, conjugation of the metabolite with glucuronic acid, secretion of the conjugate in bile, liberation of the free N‐hydroxy compound, the postulated active intermediate, by action of bacterial flora in large intestine where reaction with significant tissue, cell, and molecular elements occurs. After oral intake of cycasin the aglycone methylazoxymethanol is likewise freed for reaction in colon by bacterial enzymes. 1,2‐Dimethylhydrazine yields azoxymethane which is hydroxylated in liver, conjugated with glucuronic acid and secreted in bile, again to be split in gut with liberation of the active methylazoxy‐methanol. On the basis of these models, colon cancer formation in man may involve: 1. ingestion of complex carcinogens with diet, with liberation of the active agent by bacterial enzymes; 2. ingestion of procarcinogens, absorption, metabolism by liver, secretion in bile, and freeing of active agent in gut; 3. production of active agent by bacterial flora in gut by conversion of select food precursors, and 4. production of a mycotoxin by an intestinal microorganism.

Effects of Moquiniastrum polymorphum ssp floccosum ethnolic extract on colorectal carcinogenesis induced by 1,2-dimethylhydrazine

“…DMH is classified as a pro-carcinogen agent, that is, it requires metabolic activation to become an active carcinogen (LaMont and O'Gorman, 1978), and the activation mainly occurs in the liver, with oxidation of DMH in azomethane and, subsequently, in azoxymethane, which, in turn, is converted into methyl-azoxymethane (Weisburger, 1971;LaMont and O'Gorman, 1978). At body temperature, methyl-azoxymethane is an unstable compound that undergoes decomposition spontaneously, giving rise to formaldehyde, water, nitrogen, and methyl diazonium, an alkylating agent that introduces a reactive carbonic ion capable of reacting with DNA, RNA, and proteins (Weisburger, 1971).…”

Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethylhydrazine (DMH)

“…The model of induction using subcutaneous DMH is a very well known and experimented model (19,20) used to obtain tumors resembling human colorectal cancer, both microscopically and in clinical behavior (18). Most authors consider that only one dose of 20 mg per kilogram of weight, injected weekly for 26 weeks, may induce a very high incidence of colorectal adenocarcinomas (18,19,(21)(22)(23)(24).…”

The Alkylation of Nucleic Acids of Rat and Mouse In Vivo by the Carcinogen 1,2-Dimethylhydrazine

“…The formald.ehyde was assayed by the method of MacFadyen (1945). Included in this measurement would be the formaldehyde produced from any /8-glucuronide of methylazoxymethanol present as postulated by Weisburger (1971 WAeisburger's hypothesis. This finding for 1,2-dimethylhydrazine is in contrast to that with another colon carcinogen 3-2'-dimethyl-4-aminobiphenyl (Spjut and Noall, 1970).…”

“…The similarities in the metabolism of 1,2-dimethylhydrazine and other carcinogens such as cycasin and dimethylnitrosamine, for which the same ultimate carcinogenic metabolite has been postulated, have been discussed previously (Preussmann et al, 1969;. Weisburger (1971) has proposed that 1,2-dimethylhydrazine induces colon tumours because it is metabolized in the liver to methylazoxymethanol (the proximate carcinogen of cycasin) and excreted as the glucuronide in the bile; the conjugate is postulated to be hydrolysed by enzymes of the gut flora, releasing methylazoxymethanol at the site of tumour productioin. 1,2-Dimethylhydrazine has previously been shown to methylate mouse liver and colon nucleic acids in vivo whilst Kruger, Wiessler and Rucker (1970) (Hawks et at., 1971).…”