Methylazoxymethanol

Kate K, Kawai T, Fuji M, et al. 1985. Enhancing effect of preadministration of carbon tetrachloride on methylazoxymethanol acetate-induced intestinal carcinogenesis. J Toxicol Sci 10 289-293. 

The natural-occurring carcinogen cycasin, which is a glycoside of methylazoxymethanol (Fig. 1.1), is hydrolyzed by the gut bacteria after oral administration. The product of the hydrolysis is methylazoxymethanol, which is absorbed from the gut and which is the compound responsible for the carcinogenicity. Given by other routes, cycasin is not carcinogenic, as it is not hydrolyzed. 

Cycasin is a glucose conjugate of methylazoxymethanol. When hydrolyzed by the enzymes found in the gut, it releases methylazoxymethanol, which is carcinogenic. When the cycasin is given by other routes, i.p., for example, it is not hydrolyzed and so is not carcinogenic. 

Table 9. Effect of methylazoxymethanol acetate on Sprague-Dawley and Lobund Wistar rats...

Dimethylhydrazine is metabolized by a sequence of oxidation steps, first dehydrogenation to azomethane, A -oxidation of this to azoxymethane and finally a C-oxidation to methylazoxymethanol (Fiala, 1975, 1977). This last metabolite decomposes to give the highly reactive methyldiazonium ion to which the carcinogenicity of the compound has been attributed. The sequential nature of these oxidation steps has been shown in the isolated perfused rat liver (Wolter Frank, 1982). Fiala (1977) showed that the C-oxidation of azoxymethane to methylazoxymethanol is catalysed by hepatic microsomes, while Schoental (1973) found that methylazoxymethanol was converted to the corresponding aldehyde by an NAD-dependent dehydrogenase. 

Dimethylhydrazine is readily absorbed. It can be A -dein ethylated, yielding formaldehyde, and can be oxidized through several steps to yield methylazoxymethanol. It binds covalently to protein, DNA and RNA in many mammalian tissues. The colon of rats is a target organ for 1,2-dimethylhydrazine toxicity, where it can produce aberrant crypts. In developmental studies, it is embryo- and feto-toxic in rats. 

Pollard, M. Zedeck, M.S. (1978) Induction of colon tumors in 1,2-dimethylhydrazine-resistant Lobund Wistar rats by methylazoxymethanol acetate. J. natl Cancer Inst., 61. 493-494 Pozharisski, K.M., Kapustin, Y.M., Likhachev, A.J. Shaposhnikov, J.D. (1975) The mechanism... 

Figure 8.7 Bioactivation of cycasin by intestinal microflora to the carcinogen methylazoxymethanol.

Methyl-ONN-azoxy) methyl (3-D-glucopyranoside, methylazoxymethanol (3-D-glucoside, P-D-glucosyloxyazoxymethane. 

Methylazoxymethanol acetate trans-5-Amino-3[2-(5-nitro-2- Mouse Large intestine... 

Banner et al., (21) found that selenium did not influence the acute alterations induced by 2-acetylaminofluorene or methylazoxymethanol and suggested that the anticarcinogenic properties of selenium were due to a mechanism other than an interference with carcinogen activation and interaction with cellular macromolecules. 

Table IV. Effect of dietary protein concentration on host mediated mutagenicity of dimethylhydrazine (DMH), azoxy-methane (AOM) and methylazoxymethanol (MAll) in C57BL/6 x C3HF1 male mice...

Of critical concern is the possibility that developmental exposure may result in an acceleration of age-related decline in function. Animal studies have demonstrated that developmental exposure to neurotoxicants such as methylmercury, methylazoxymethanol, and ethanol may cause few or no neurotoxic effects in young animals, but marked effects in ageing animals. Investigations of effects in ageing animals are not included in regulatory guidelines. 

Luthman J, Eriksdotter-Nilsson M, Jonsson G (1990) Structural and neurochemical effects in mouse cerebellum following neonatal methylazoxymethanol and 6-hydroxydopamine treatment. Int J Dev Neurosci 5 107-118. 

Methylazoxymethanol (Euphorbiaceae) [seed] From deglvcosylation of Cycasin DNA reaction breakage... 

---