Comparative genotoxicity of nitrogen mustard and nor-nitrogen mustard

Abstract

Nitrogen mustard and nor-nitrogen mustard were investigated in Salmonella typhimurium and human lymphocytes for genotoxicity. Point mutations were assessed using the plate test, the conventional spot test and a method in which the substances were not in direct contact with the microorganisms. Both compounds were active, but nor-nitrogen mustard was far more potent than nitrogen mustard in all bacterial systems. Cytogenetic experiments with human lymphocytes revealed that both compounds induced a dose dependent increase in chromosomal aberrations and sister chromatid exchanges, but that nitrogen mustard was 10 times more potent than nor-nitrogen mustard. Thus, the spectrum of activity for nor-nitrogen mustard and nitrogen mustard differ. Nor-nitrogen mustard was more effective in inducing point mutation damage than nitrogen mustard and a reversal of potency was found for cytogenetic damage. These results indicate that although these two substances induce the same type of DNA lesions the amounts of the different DNA adducts vary.

Occupational Exposure To Nor-Nitrogen Mustard: Chemical and Biological Monitoring

“…Slides for chromosome analysis were made according to Hartley-Asp and Hyldig Nielsen (1984). Slides for SCE analysis were immersed for 12 min in 0.5 pg/ml bisbenzimide (Hoechst 33258), mounted directly, and illuminated for 2 hr under UVA light, and then stained for 5 min in 2% Giemsa.…”

“…' Nor-nitrogen mustard (nor-NH2) is an alkylating agent which has been shown to induce mutations in Salmonella typhimurium and cause increases in chromosome aberrations (CAs) and SCEs in human lymphocytes in vitro (Hartley-Asp and Hyldig-Nielsen, 1984). It is handled in kilogram quantities in various manufacturing plants throughout the world as a major precursor in the production of cyclophosphamide and estramustine phosphate, two chemotherapeutic agents.…”

Enhancing DNA Crystal Durability through Chemical Crosslinking

“…Bis(2‐chloroethyl)amine (nornitrogen mustard; NOR) is a DNA alkylating agent capable of interstrand crosslinking . It is the primary active agent in cyclophosphamide and, like other nitrogen mustards, it preferentially alkylates the N7 position of purines, with guanosine having a higher crosslinking efficiency than adenosine . With two functional groups capable of going through the azirdinium intermediate, NOR reactivity can result in mono‐ or dialkylation, with the latter potentially leading to intra‐ or interstrand crosslinks.…”

“…[44,45] It is the primary active agent in cyclophosphamide and, like other nitrogen mustards, it preferentially alkylatest he N7 position of purines, with guanosine having ah igher crosslinkinge fficiency than adenosine. [44,[46][47][48] With two functional groups capable of going throught he azirdinium intermediate, NORr eactivity can result in mono-or dialkylation, with the latter potentially leadingt oi ntra-or interstrand crosslinks.N OR has al imited half-life in solution,( 20 min at 37 8C), [49] due to reactivity in water to form bis(2-hydroxyethyl)amine. To our knowledge,t he interstrand crosslinking potentialo fN OR or other nitrogen mustards with DNA crystalshas not been examined.…”