Mutagenicity, Metabolism, and DNA Interactions of Urethane

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Abstract
Urethane, a known animal carcinogen, has been the subject of intensive research efforts spanning 40 years. Recent concerns have focused on the presence of urethane in a variety of fermented foods and alcoholic beverages, although no epidemiological studies or human case reports have been published. Much information is available about the mutagenesis, metabolism, and DNA interactions of urethane in experimental systems. Urethane is generally not mutagenic in bacteria although in some instances it acts as a weak mutagen. Urethane is not mutagenic in Neurospora but is weakly mutagenic in Saccharomyces. Drosophila appear to be the only organisms that consistently give positive mutagenic results with urethane, but its mutagenicity is weak and in many cases shows no clear dose dependence. Urethane is a good clastogen in mammalian somatic cells in vivo, but it shows variable results with cells in vitro. It efficiently induces sister chromatid exchanges in a variety of cells. Mammalian spermatogenic cells are insensitive to the induction of specific locus and dominant lethal mutations by urethane. Mutational synergism has been reported to occur between ethyl methanesulfonate and urethane when administered two generations apart, and some investigators have suggested possible synergism for cancer-causing mutations in mice exposed to X-rays and urethane one generation apart. These studies are controversial and have not been confirmed. Studies on the induction of cancer-causing dominant mutations by urethane are at variance with results from extensive studies with the specific locus test in mice. Urethane studies with the unscheduled DNA synthesis assay in mouse spermatogenic cells and with the sperm abnormality test have given negative results. Urethane is rapidly and evenly distributed in the body. The rate of elimination of urethane from plasma is a saturable process and varies according to the strain and age of the animal. Recent studies have concentrated on the effect of ethanol on urethane metabolism. At concentrations similar to those in wine, ethanol inhibits the tissue distribution of urethane in mice. These results are important because they suggest a lower carcinogenic/mutagenic risk than expected from exposure to urethane in alcoholic beverages. Although research on the metabolic activation of urethane has been extensive, no conclusive results have been obtained about its active metabolite, at one time thought to be N-hydroxyurethane. More recently, it has been postulated that urethane is actived to vinyl carbamate and that this metabolite is capable of reacting with DNA. Vinyl carbamate is more carcinogenic and more mutagenic than the parental compound, but despite intensive efforts it has not been identified as a metabolite in animals treated with urethane. Urethane binding to DNA appears to correlate well with tissue susceptibility to cancer. Various studies have attempted to elucidate the molecular nature of the bound molecule and the binding site. Some results have indicated the formation of a single DNA adduct, 7-(2-oxoethyl)guanine. This adduct may isomerize to O6,7-(1'-hydroxyethano)guanine, which might be more mutagenic than the 2-oxoethyl adduct; however, this possibility seems unlikely. Despite extensive research, urethane's metabolism and molecular mechanisms of mutation are still not clearly understood.

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