Is neurodegenerative disease a long-latency response to early-life genotoxin exposure? (1/4)

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Mutagenicity of the naturally occurring carcinogen cycasin and synthetic methylazoxymethanol conjugates in Salmonella typhimurium. (2/4)

The aglycone methylazoxymethanol of the naturally occurring carcinogenic glucoside, cycasin, has previously been shown to be mutagenic, but cycasin per se has not. In this work, cycasin was demonstrated to be mutagenic using a modification of the Ames Salmonella test in which it was preincubated with beta-glucosidase and the tester strain in liquid medium. The mutagenicity of cycasin to six histine-depedent Salmonella strains varied considerably with strain HisG46 being the most susceptible. Methylazoxymethyl-beta-D-glucosiduronic acid, which also is nonmutagenic per se, similarly became mutagenic when preincubated with beta-glucuronidase. Methylazoxymethyl acetate, which is slightly mutagenic by the Ames standard pour plate method, became highly mutagenic on preincubation. The mutagenicity of free methylazoxymethanol was confirmed, and a linear dose-response relationship was observed. The common conditions required for activation of nonmutagenic methylazoxymethanol conjugates, the glucoside cycasin and methylazoxymethyl-beta-D-glucosiduronic acid, are 90-min preincubation at 30 degrees, pH 6.5, with an appropriate hydrolase and Salmonella typhimurium HisG46.  (+info)

DNA fragmentation in some organs of rats and mice treated with cycasin. (3/4)

Cycasin (methylazoxymethanol-beta-D-glucoside) is carcinogenic in several animal species. It produces a variety of malignant tumours, mainly in the liver of mice, and in the liver, kidney and large intestine in rats. It does not appear to be mutagenic in the Ames test, even in the presence of liver microsome fraction, and it is among those carcinogens (less than 10%) ranked as "false negatives" in this test. The ability of cycasin to damage in vivo liver, kidney, lung and colonic DNA of Wistar rats and C57BL/L mice was investigated by means of alkaline elution technique. Oral single-dose administration of cycasin, in the range of 50-400 mg/kg body weight, produced in the rat a clearly evident dose-dependent DNA fragmentation in the liver, and less marked damage to DNA from kidney and colon mucosa. In mice, the same treatment produced dose-dependent DNA damage only in the liver. DNA repair up to 18 h appeared to be incomplete both in mice and rats. Methylazoxymethanol acetate is considered to be an active form of cycasin. While in vivo methylazoxymethanol acetate caused DNA damage, in vitro it appeared inactive and required metabolic activation, possibly consisting in its hydrolysis by esterase activity, to be able to cause DNA fragmentation.  (+info)

Activation of cycasin to a mutagen for Saccharomyces cerevisiae by rat intestinal flora. (4/4)

Genetic test systems involving microorganisms and liver enzyme preparations may be insufficient to detect compounds that require breakdown by enzymes provided by the microbial flora of the intestinal tract. A method is described for providing such activation and for simultaneously testing the potential genetic activity of breakdown products in an indicator organism. Parabiotic chambers containing Saccharomyces cerevisiae genetic test organisms in one chamber were separated by a membrane filter from rat cecal organisms and test chemical contained in the other chamber. The genetic activities of cycasin breakdown products for mutation, gene conversion, and mitotic crossing-over in samples incubated aerobically are reported. Samples containing cycasin alone had a small but clearly increased frequency of genetic damage. Samples containing rat cecal organisms without cycasin showed no increase in genetic activity. Anaerobic incubation resulted in no increase in genetic activity in any of the samples.  (+info)