MUTAGENICITY STUDIES IN SALMONELLA-TYPHIMURIUM ON SOME CARCINOGENIC N-NITRAMINES INVITRO AND IN THE HOST-MEDIATED ASSAY IN RATS

  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (8) , 3205-3210
Abstract
N-Nitrodimethylamine, N-nitrodiethylamine, N-nitromorpholine and their N-nitroso analogs, N-nitrosodimethylamine, N-nitrosodiethylamine and N-nitrosomorpholine, were tested in S. typhimurium strains TA100 and TA1530. The mutagenicity of all compounds, except N-nitrodiethylamine, was demonstrated in liquid incubation assays in at least 1 tester strain; 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 .apprx. 10 times less mutagenic and N-nitrodimethylamine .apprx. 10 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 3 nitramines was determined in the host-mediated assay in rats. After p.o. [oral] 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 h. All 3 nitramines were 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. Carcinogenic nitramines apparently exert their mutagenic effects through the formation of alkylating intermediates.