Bela Toth

Lack of tumorigenicity of sodium benzoate in mice

Sodium benzoate was administered as a 2% solution in drinking water for life to randomly bred Swiss mice. Consumption of the chemical caused no detectable tumorigenic effect under the current experimental conditions.

8-Arylguanine adducts from arenediazonium ions and DNA

Arenediazonium ions (ArN2+) are genotoxic though the source of their genotoxicity is unknown. The present studies were undertaken to determine if reductive decomposition of ArN2+ to aryl radicals (Ar) in the presence of calf thymus DNA (ctDNA) or in cells results in the formation of DNA adducts. We found that when arenediazonium ions of the general structure p-X-ArN2+ (X = CH3, CH2OCH3, CH2OH) are allowed to react with ctDNA or incubated with cells under conditions that produce p-X-Ar, DNA adducts are formed with guanine. The structure of the adduct is the C8-substitution product derived from guanine and p-X-Ar. Formation of p-X-Ar was determined by ESR spin-trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO). The extent of C8-arylguanine adduction was measured by high performance liquid chromatography (HPLC) analysis of the DNA hydrosylate and comparison with authentic synthetic standards. The C8-arylguanine adducts observed to form may be important in regard to the genotoxicity of ArN2+, though other DNA adducts such as the N6-triazene of adenine or C8-aryladenine adducts can form. Finally, though the formation of C8-arylguanine adducts from arenediazonium ions has been proposed, this is the first report demonstrating their formation in DNA.

Lack of Carcinogenicity of Nicotinamide and Isonicotinamide following Lifelong Administration to Mice

Nicotinamide and isonicotinamide were administered separately as 1% solutions continuously in drinking water to 6-week-old randomly bred Swiss mice for their life span. Consumption of these chemicals caused no apparent carcinogenic action under the present experimental conditions.

Chemical oxidation and metabolism of N-methyl-N-formylhydrazine. Evidence for diazenium and radical intermediates

N-Methyl N-formlhydrazine (1), a component of the mushroom Gyromitra esculenta, is a carcinogen. Its mode of action, however, is poorly understood. To determine the intermediates that may form during the metabolism of 1, we examined its oxidative chemistry, identified the products and inferred the intermediates on the basis of these products. The incubation of 1 with rat liver microsomes was also studied and the metabolites determined and quantified. Both the chemical and the microsome-mediated oxidation of 1 yielded formaldehyde and acetaldehyde. The formation of acetaldehyde requires (i) the oxidation of 1 to a diazenium ion (I) or diazene (II) and (ii) fragmentation of I/II to formyl and methyl radicals. It is suggested that these radical intermediates may be important in understanding and elucidating carcinogenesis by 1.

Anomalous reaction of adenine and 4-(hydroxymethyl)benzenediazonium ion

The reaction of 1a with 2 is unique in that 1a is capable of being an oxidant, generating 1f in situ. The mechanism and biological consequences of the reaction are discussed.

1,2-Diallylhydrazine Dihydrochloride Carcinogenesis in Mice

Continuous administration of 0.0625% 1,2-diallylhydrazine dihydrochloride in drinking water for life to 6-week-old randomly bred to Swiss mice induced lung tumors. In comparison with the untreated controls, the lung tumor incidence rose from 25 to 80% in the females and from 26 to 80% in the males. The treatment had no apparent effect on the development of other tumor types. Histopathologically, the lesions were classified as adenomas and adenocarcinomas of the lungs. The work is a continuation of our structure activity inquiry concerning the relative carcinogenic potencies of the dialkyl versus the monoalkyl series of hydrazine analogues.

Effects of Lifelong Administration of β-Phenylisopropylhydrazine Hydrochloride and Thiocarbamylhydrazine in Mice

beta-Phenylisopropylhydrazine hydrochloride and thiocarbamylhydrazine were separately administered as 0.0312 and 0.0156% solutions in drinking water for life to randomly bred Swiss mice. The consumption of the chemicals resulted in no detectable tumorigenic effects in the treated animals, and it is therefore concluded that these compounds are apparently noncarcinogenic under the present experimental conditions.