Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals: discussion.

192

Summary.-Although many carcinogens are mutagens, there is no direct evidence that the cancer-cell phenotype is the result of gene mutation. Transplantation experiments have strongly indicated that malignant cells can arise or revert to the normal phenotype in the absence of mutation. It is suggested that damage to DNA followed by repair triggers the epigenetic changes in gene expression which are responsible for malignancy. We previously proposed that methylation of specific DNA sequences adjacent to structural genes determines whether or not transcription will occur. Specific methylases are required for the switching on of genes and for the stable maintenance of the methylated state, which provides a basis for the control of gene expression in differentiated cells. It is now seen that damage to DNA followed by repair, just before or just after DNA replication, can lead to the loss of methyl groups. This can induce a switch in gene activity which is heritable, but potentially reversible. The known large difference in the probability of malignant transformation in cells of rodents and large mammals is hard to explain if mutation is responsible. On the other hand, this new theory provides an explanation for this difference, since the probability of epigenetic changes in gene activity will depend on the activity of methylating enzymes and the rate of excision repair. The theory is supported by the evidence that excision repair is more efficient in cultured fibroblasts from large long-lived animals than from small short-lived ones.

mentioning

confidence: 99%

A new theory of carcinogenesis

Holliday¹

1979

192

“…In fact, cycasin is (Kobayashi & Matsumoto, 1965;Laqueur & Spatz, 1968) whilst its carcinogenic activity by s.c. injection is restricted to the early postnatal period, due to the transient presence in newborns of a glucosidase in the subcutaneous tissue (Spatz, 1968;Shibuya & Hirono, 1973). Moreover, cyeasin, because of the glucosidase requirement for its activation, is non-mutagenic in the Ames Salmonella test even in the presence of liver microsomal fraction (Smith, 1966;McCann et al, 1975;McCann & Ames, 1976) but is mutagenic in the hostmediated assay (Gabridge et al, 1969). On the contrary, methylazoxymethanol and its synthetic ester methylazoxymethanol acetate were shown to be carcinogenic in adult rats and hamsters (IARC, 1976) also by the parenteral route, and methylazoxymethanol without microsomal fraction was mutagenic in bacteria on Petri dishes (Smith, 1966).…”

Section: Discussionmentioning

confidence: 99%

“…On the contrary, methylazoxymethanol and its synthetic ester methylazoxymethanol acetate were shown to be carcinogenic in adult rats and hamsters (IARC, 1976) also by the parenteral route, and methylazoxymethanol without microsomal fraction was mutagenic in bacteria on Petri dishes (Smith, 1966). Furthermore, evidence of methylation at the N-7 position of guanine has been reported for methylazoxymethanol in vitro (Matsumoto & Higa, 1966) and for cyeasin and methylazoxymethanol acetate in vivo (Shank & Magee, 1967;Nagata & Matsumoto, 1969 (Shank & Magee, 1967) methylation of liver DNA in rats given cycasin by stomach tube. A markedly lower, but still clearly evident, damage was present in DNA of kidney and colon mucosa, the lung DNA being unaffected by doses of cycasin up to 400 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

“…This experimental evidence indicates that the alkaline elution technique allows the rapid evaluation of the DNA damage exerted in vivo by a carcinogen-like cycasin, which does not depend for its metabolic activation to a reactive intermediate on the microsomal metabolizing system. Such an ability to reveal the DNA damage, induced in vivo by compounds possessing a peculiar type of metabolic activation, has been assessed with 1 2-dimethylydrazine another carcinogen which gives false negative results with the Ames Salmnonella/microsome mutagenicity test (McCann et al, 1975;McCann & Ames, 1976).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

DNA fragmentation in some organs of rats and mice treated with cycasin

Cavanna¹,

Parodi²,

Taningher³

et al. 1979

Summary.-Cycasin (methylazoxymethanol-p-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/6 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.CYCASIN (methylazoxymethanol-,B-Dglucoside), which occurs in cycad plants used by some populations as food, has been reported to be carcinogenic in rodents (mice, rats, hamsters, guinea-pigs and rabbits) (IARC, 1976 Brambilla et al., 1978). A ranking tabulation of doserelated DNA damage induced by cyeasin in rats has been preliminarily reported . MATERIALS AND METHODSIn these experiments C57BL/6 male mice and Wistar male rats, aged 1-2 months, were used. Cycasin (a gift from Dr H. Matsumoto, University of Hawaii at Manoa, Honolulu) was dissolved in distilled water and administered orally by gastric intubation at varying single-dose levels and intervals before animals were killed by cervical dislocation and exsanguinated. Methylazoxymethanol acetate (ICN Pharmaceuticals, Inc., Plainview, New York, U.S.A.) was dissolved in physiological saline and injected i.p. into C57BL/6 male mice. Liver, kidneys, lungs and descending colon were quickly removed and rinsed in

“…There is consequently great current interest in various short-term assays that, though not capable of proving the carcinogenicity of a compound, may be valuable as screening tests. Of the battery of tests considered necessary for adequate prescreening, at present the most useful appear to be those which detect chemically-induced reversion to prototropy in amino-acid-requiring mutants of Salmonella typhimurium and Escherichia coli. These test have been developed particularly by Ames and his colleagues, who have reported the results of testing some 300 carcinogenic and non-carcinogenic compounds (McCann et al, 1975;McCann and Ames, 1976).…”

mentioning

confidence: 99%

Effects of repeated applications of two semi-permanent hair dyes to the skin of A and DBAf mice

Searle¹,

Jones²

1977

Summary.-Two proprietary semi-permanent hair dyes were tested for carcinogenicity in A and DBAf mice by repeated topical applications in aqueous acetone. Mice of both strains developed lymphoid tumours but experimental differences were marked only in DBAf mice. A number of tumours of the ovary and uterus, and some skin papillomas near the penis, occurred in dye-treated but not in control DBAf mice. As many hair-dye constituents are known mutagens, adequate carcinogenicity testing of these substances, and epidemiological study of exposed human populations, are needed for evaluating possible health hazards from hair dyeing.