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PubMed1990

Mutagenicity, metabolism, and DNA interactions of urethane.

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 Nuerospora 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 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 activated to vinyl carbamate and that this metabolite is capable of reacting with DNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1982

Urethane inhibits cardiovascular responses mediated by the stimulation of alpha-2 adrenoceptors in the rat.

Clonidine and oxymetazoline (4.0 microgram/kg i.v. or i.a.) evoked a marked bradycardia in either methylatropine-pretreated conscious or pentobarbital-anesthetized (55 mg/kg i.p.), vagotomized rats. Urethane (1.2 g/kg i.p.) inhibited by more than 50% this effect which is mediated through the stimulation of peripheral and/or central neuronal alpha-2 adrenoceptors. However, in adrenalectomized rats only the inhibition of oxymetazoline by urethane was significantly less pronounced. In pithed rats in which the adrenal glands were either left untouched or surgically removed, urethane significantly attenuated the clonidine or oxymetazoline-induced decreases in experimental neural sympathetic tachycardia although it neither changed the base-line nor the experimentally elevated heart rate. Urethane, in contrast to pentobarbital, increased plasma epinephrine concentrations in intact but not in adrenalectomized or in pithed rats. Elevation of plasma epinephrine did not result from the low arterial pressure level associated with urethane anesthesia since the increase of this parameter with vasopressin did not abolish the effect of urethane. Furthermore, guanethidine-pretreated rats, when anesthetized with urethane, exhibited a higher heart rate and plasma adrenaline value than those anesthetized with pentobarbital. The elevated heart rate was decreased by either propranolol or adrenalectomy. The bradycardia produced by injecting clonidine into the lateral cerebral ventricles of either intact or adrenalectomized rats was markedly less in urethane- than in pentobarbital-anesthetized animals. Whereas in pentobarbital-anesthetized rats the peak heart rate effects of i.v. or i.c.v. clonidine were similar, in urethane-anesthetized animals the effects of clonidine were more inhibited when it was given centrally than when it was given peripherally. In pithed rats, the cumulative dose-pressor response curves elicited by the relatively selective alpha-2 adrenoceptor agonists, B-HT 930 and M-7, were depressed by urethane significantly more than those produced by the relatively selective alpha-1 adrenoceptor agonists, phenylephrine and cirazoline, or by angiotensin II. Urethane also decreased the pressor responses evoked by clonidine, oxymetazoline and norepinephrine which stimulate both alpha-1 and alpha-2 adrenoceptors. However, the extent of this inhibition was less than that of B-HT 920 and M-7 but greater than that of cirazoline and phenylephrine. These results show that urethane inhibits cardiovascular responses that are mediated by peripheral and central alpha-2 adrenoceptors. Furthermore, urethane increases the central drive to the adrenal medulla and this leads to the secretion of epinephrine. This may be partly responsible for the inhibitory activity of urethane on oxymetazoline-induced bradycardia. Although the basic mechanism by which urethane impairs responses mediated by alpha-2 adrenoceptors remains to be determined, it is advised that urethane anesthesia should be avoided, particularly for cardiovascular studies.

Adrenalectomy↗