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Mutagenicity Studies in Salmonella typhimurium on Some Carcinogenic N-Nitramines in Vitro and in the Host-mediated Assay in Rats¹

Division of Environmental Carcinogenesis, International Agency for Research on Cancer, 150 cours Albert-Thomas, F-69372 Lyon Cédex 2, France

N-Nitrodimethylamine, N-nitrodiethylamine, N-nitromorpholine and their N-nitroso analogs, N-nitrosodimethylamine, N-nitrosodiethylamine, and N-nitrosomorpholine, were tested in Salmonella typhimurium strains TA100 and TA1530. The mutagenicity of all compounds, except N-nitrodiethylamine, was demonstrated in liquid incubation assays in at least one of the tester strains; it required the presence of a postmitochondrial supernatant from the liver of Aroclor-treated rats, reduced nicotinamide adenine dinucleotide phosphate-generating system, and oxygen. When compared on a molar basis with their N-nitroso analogs, N-nitromorpholine was about 10 times less mutagenic and N-nitrodimethylamine about 70 times less mutagenic. Addition of disulfiram to the assays at a final concentration of 0.1 mM efficiently inhibited mutagenesis by all nitro and nitroso compounds; ascorbic acid at a 7.4 mM concentration produced less inhibition.

Mutagenic activity of the three nitramines was also determined in the host-mediated assay in rats. After p.o. administration of each of the N-nitramines, cells of S. typhimurium strains TA1530 and TA100 that had been injected i.p. were isolated from the peritoneal liquid after 1, 3, and 6 hr. All three nitramines were found to be mutagenic for strain TA1530 but not for TA100. Mutation frequencies (number of histidine revertants per 10⁶ surviving cells) were in the descending order N-nitromorpholine > N-nitrodimethylamine > N-nitrodiethylamine. After a p.o. dose of N-nitrodiethylamine to rats, bacteria were also isolated from liver, lungs, and kidneys. Mutation frequency was highest in bacteria recovered from the liver but was not increased in those obtained from lungs and kidneys. The data suggest that carcinogenic nitramines exert their mutagenic effects through the formation of alkylating intermediates.

¹ Partially supported by National Cancer Institute Contract N01-CP-55630 from the National Cancer Institute, NIH, Bethesda, Md.

² Visiting scientist at International Agency for Research on Cancer from the N. N. Petrov Research Institute of Oncology, Leningrad, USSR (under a WHO fellowship 1979–1980).

³ To whom requests for reprints should be addressed.

Received 5/28/80. Accepted 4/22/81.