The cytotoxic and carcinogenic potential of alkylating Nnitroso compounds is thought to be derived from their propensity to degrade to fragments in which the Nnitroso bond remains intact. Recent work, however, has revealed degradation pathways in which this bond is dissolved. This denitrosation is a detoxification process. Denitrosation could be a significant factor in the in vivo metabolism of Nnitroso compounds and potentially could be modulated advantage. We have been studying nitrosocimetidine (NC), the N-nitrosated derivative of cimetidine (Tagamet), a drug ingested by tens of millions of people for the treatment of stomach ulcers. NC has the same N-methylNnitroso grouping as contained in the carcinagens dimethylnitrosamine, methylnitrosourea and 1methyl-2-nitro-1-nitrosoguanidine. It is capable of methylating DNA in vitro, generating the same pattern of alkylation products as the noted carcinagens, and gives positive indications in the several shortterm tests for carcinogenic potential. However NC has been judged to be a weak or noncarcinagen when administered to rats or mice and we have found that, in fact, NC is nearly 100 percent denitorsated upon administration to rats or hamsters. We have thus far identified three NCdenitrosating activities: glutathione transferase, the cysteine residues on hemoglobin and a microsomal activity tentatively identified as NADPHcytochrome P450 reductase. As an aid in our evaluation of these activities we are in the process of synthesizing a series of 1,3dimethyl1nitrosoguanidines variously 2-position substituted which we anticipate will be differentially vulnerable to denitrosation. Using NC, these analogues and a range of other Nnitroso compounds we propose to detail the in vitro properties of the denitrosating activities using spectral kinetic analysis and chromatographic reaction product analysis. We will also identify and evaluate inhibitors and enhancers of these activities.
Our aim will be to elucidate the chemical properties of N-nitroso compounds which dictate their susceptibility to denitrosating activities and to compare these activities as they mediate what we sense is a common reductive denitrosation reaction. Armed with this understanding of the in vitro chemistry and with our several compounds we will continue our work with rats and hamsters with the hope of determining the relative importance of the various denitroasating activities and how they might be modulated.
|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 (1987) Evidence for cytosolic glutathione transferase-mediated denitrosation of nitrosocimetidine and 1-methyl-2-nitro-1-nitrosoguanidine. Carcinogenesis 8:1791-800|
|Jensen, D E; Stelman, G J; Spiegel, A (1987) Species differences in blood-mediated nitrosocimetidine denitrosation. Cancer Res 47:353-9|
|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|