Mutational specificities of N-nitrosamines in a host-mediated assay: comparison with direct-acting N-nitroso compounds in vitro and an approach to deducing the nature of ultimate mutagens in vivo.
The mutational activities and specificities of several N-nitrosamines in Salmonella recovered from mouse liver in the host-mediated assay (HMA) were compared with the specificities of related direct-acting N-nitroso compounds in vitro. The specificities of the direct-acting methyl, ethyl, propyl, and 2-hydroxypropyl compounds were all different and presumably are attributable to the DNA adducts resulting from the corresponding alkyldiazonium or carbonium ions. Introduction of a 2-hydroxyl group greatly influenced the mutational specificity. The 2-oxopropyl compound showed the same specificity as the methyl compound. This result is consistent with one of the known breakdown pathways of the oxopropyl diazonium ion (or related reactive species), which leads to a methyl diazonium ion. The N-nitrosodialkylnitrosamines N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and N-nitrosodipropylamine (NDPA), which all require metabolic activation, showed specificities in the HMA similar to those of their direct-acting counterparts. The cyclic nitrosamine N-nitrosopyrrolidine was weakly active in the HMA, although its direct-acting derivative was a potent mutagen in vitro. The results for NDMA and NDEA were consistent with most previous studies of the metabolism of these compounds in vivo. However, NDPA can yield methylating, and probably hydroxypropylating, species in addition to propyldiazonium ion. As the specificity of NDPA was similar to that of a propylating agent, NDPA appears to lead to genotoxic products in the mouse liver mainly by direct alpha-hydroxylation. The initial results described here indicate that mutational specificity in the HMA can be used to deduce metabolic pathways leading to genotoxic products when the appropriate proximate mutagens are available as standards. Furthermore, we observed a reasonable correlation between potency in the HMA and hepatocarcinogenesis.
Liu
Y X
YX
Biochemistry/Microbiology Unit, New York University Dental School, New York 10010.
Guttenplan
J B
JB
D000818:Animals; D001482:Base Composition; D001711:Biotransformation; D008099:Liver / Q000378:metabolism; D051379:Mice; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D009602:Nitrosamines / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
D009153:Mutagens; D009602:Nitrosamines; D009603:Nitroso Compounds