The widely used drug cimetidine (""""""""Tagamet"""""""") can be nitrosated in the presence of nitrite and under mild acid conditions to form a compound, nitrosocimetidine (NC), which has a chemical structure very similar to those of the mutagens and laboratory carcinogens N-methyl-N feet-nitro-N-nitrosoguanidine (MNNG) and methylnitrosourea (MNU). NC has given positive indications in several short-term tests for possible carcinogenic activity and is capable fo methylating DNA in a manner identical to that of MNNG and of MNU. Nevertheless, NC has been found to be a weak or noncarcinogen and to be very poor at modifying DNA in vivo. Our experiments have indicated that NC, like MNNG, decomposes very rapidly in the presence of thiol compounds. Much of this decomposition is denitrosation. The compound also rapidly decomposes in isolated whole blood and in purified hemoglobin solutions. In both cases denitrosation predominates. We have discovered that incubation of NC with hemoglobin produces nitrosylhemoglobin and have demonstrated hemoglobin cysteine residue involvement. We suspect that hemoglobin-mediated denitrosation limits the in vivo activity of NC. Our hypothesis is that the strong electron-withdrawing cyano group in NC promotes, in the presence of thiol, both decomposition to produce a methylating species and decomposition by denitrosation. Denitrosation predominates. MNNG also has an electron-withdrawing group, the nitro moiety, and in this case methylating species production prevails. To test our supposition and to establish the range of compounds over which the denitrosation phenomenon might have effect, we propose to synthesize a series of 1,3-dimethyl-1-nitroso compounds which contain substituents with different electron-withdrawing capacity. We will establish their in vitro degradation properties and their in vivo DNA alkylating potential. We will also continue our study of nitrosylhemoglobin formation. Finally we propose to use this same series of compounds, which we anticipate will have differential thiol sensitivity, to determine the role of intracellular glutathione in nitroso compound activation, inactivation and reactive intermediate scavenging.
| Jensen, D E; Stelman, G J; Williams, A W (1990) Microsomally-mediated denitrosation of nitrosoguanidinium compounds. Carcinogenesis 11:1075-82 |
| Jensen, D E; Mackay, R L (1990) Rat, mouse and hamster isozyme specificity in the glutathione transferase-mediated denitrosation of nitrosoguanidinium compounds. Cancer Res 50:1440-8 |
| Jensen, D E; Stelman, G J; Spiegel, A (1987) Species differences in blood-mediated nitrosocimetidine denitrosation. Cancer Res 47:353-9 |
| Jensen, D E; Stelman, G J (1987) Evidence for cytosolic glutathione transferase-mediated denitrosation of nitrosocimetidine and 1-methyl-2-nitro-1-nitrosoguanidine. Carcinogenesis 8:1791-800 |
| Ogiu, T; Hard, G C; Magee, P N et al. (1986) Comparison of the acute toxicity of N-nitrosocimetidine with three structurally related carcinogens in the rat. Toxicol Pathol 14:395-403 |
