Effect of the esophageal carcinogen methylbenzylnitrosamine and of a putative potentiating factor, a trichothecene mycotoxin, on O6-methylguanine-dna methyl transferase in rat esophagus and liver.
Epidemiological evidence from China and South Africa has implicated Fusaria mycotoxins in the etiology of esophageal cancer, although treatment of animals with extracts of Fusaria cultures did not cause cancer of the esophagus. Fusaria are the major producers of trichothecenes, and animal experiments have shown that these mycotoxins can damage the esophagus but they have not been shown to cause esophageal cancer. A plausible concept is therefore that esophageal cancer is initiated by the potent environmental esophageal carcinogens, certain nitrosamines, but that the levels of exposure are too low to cause clinical cancer unless their effects are enhanced by additional risk factors. Among the most likely enhancing factors in the regions mentioned above are Fusaria mycotoxins. As trichothecenes are known to inhibit sulphydryl-dependent reactions and to inhibit protein synthesis, experiments were carried out to determine whether potentiation of cancer could be mediated via inhibition of the DNA repair protein O6-methylguanine-DNA methyl transferase (O6MG-MT). The effect of diacetoxyscirpenol (DS) on O6MG-MT was studied. Chronic or acute treatment with DS did not alter the level of O6MG-MT in esophagus, or affect the depletion which occurs after injection of methylbenzylnitrosamine, or alter the rate of reappearance of O6MG-MT. A high dose of DS induced O6MG-MT in liver. These results suggest that if trichothecenes are risk factors for esophageal cancer, the effect is unlikely to be mediated by inhibition of O6MG-MT. Induction of the repair protein in liver may be relevant in the animal toxicoses caused by consumption of trichothecenes, but is unlikely to be implicated in the etiology of liver cancer in man.
Craddock
V M
VM
MRC Toxicology Unit, Carshalton, Surrey, U.K.
Henderson
A R
AR
D000818:Animals; D003043:Cocarcinogenesis; D011088:DNA Ligases / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000633:toxicity; D004790:Enzyme Induction / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000139:chemically induced*; D004947:Esophagus / Q000187:drug effects / Q000201:enzymology; D005260:Female; D005670:Fusarium; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009183:Mycotoxins / Q000633:toxicity*; D011118:Polynucleotide Ligases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012717:Sesquiterpenes / Q000633:toxicity*; D014255:Trichothecenes / Q000494:pharmacology / Q000633:toxicity*
D009183:Mycotoxins; D012717:Sesquiterpenes; D014255:Trichothecenes; C014707:nitrosobenzylmethylamine; D011088:DNA Ligases; D011118:Polynucleotide Ligases; D004128:Dimethylnitrosamine; C001809:diacetoxyscirpenol