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PubMed2003

Cytochrome P450 2E1 (CYP2E1) is the principal enzyme responsible for urethane metabolism: comparative studies using CYP2E1-null and wild-type mice.

Urethane ([carbonyl-(14)C]ethyl carbamate) is a fermentation by-product in alcoholic beverages and foods and is classified as reasonably anticipated to be a human carcinogen. Early studies indicated that while CYP2E1 is involved, esterases are the primary enzymes responsible for urethane metabolism. Using CYP2E1-null (KO) mice, current studies were undertaken to elucidate CYP2E1's contribution to urethane metabolism. [Carbonyl-(14)C]urethane was administered by gavage to male CYP2E1-null and wild-type mice at 10 or 100 mg/kg and its metabolism and disposition were investigated. CO(2) was confirmed as the main metabolite of urethane. Significant inhibition of urethane metabolism to CO(2) occurred in CYP2E1-null versus wild-type mice. Pharmacokinetic modeling of (14)CO(2) exhalation data revealed that CYP2E1 is responsible for approximately 96% of urethane metabolism to CO(2) in wild-type mice. The contributions of other enzymes to urethane metabolism merely account for the remaining 4%. The half-life of urethane in wild-type and CYP2E1-null mice was estimated at 0.8 and 22 h, respectively. Additionally, the concentration of urethane-derived radioactivity in blood and tissues was dose-dependent and significantly higher in CYP2E1-null mice. High-performance liquid chromatography analysis showed only urethane in the plasma and liver extracts of CYP2E1-null mice. Because the lack of CYP2E1 did not completely inhibit urethane metabolism, the disposition of 10 mg/kg urethane was compared in mice pretreated with the P450 inhibitor, 1-aminobenzotriazole or the esterase inhibitor, paraoxon. Unlike paraoxon, 1-aminobenzotriazole resulted in significant inhibition of urethane metabolism to CO(2) in both genotypes. In conclusion, this work demonstrated that CYP2E1, not esterase, is the principal enzyme responsible for urethane metabolism.

Animals↗
PubMedDate not supplied

Inhibition of the metabolism of urethane by ethanol.

Ethanol has been shown to inhibit the localization of [ethyl-1-14C] urethane in the male mouse, but the effect of ethanol on the metabolism of urethane has not been clarified. Consequently, the concentration of unchanged urethane was determined in the blood of male mice up to 11 hr after oral administration of urethane with or without ethanol. A high and constant blood level of urethane persisted for 8 hr after the administration of an ethanolic solution of [ethyl-1-14C] urethane (125 mumol/kg, 10 muCi/20 g of mouse, 5 g of ethanol per kg, po); the blood level of ethanol was at or above 150 mg/dl during these 8 hr. In contrast, rapid clearance of radioactivity was observed in mice treated with [ethyl-1-14C]urethane dissolved in water. Coadministration of ethanol with urethane decreased the rate of 14CO2 expiration; furthermore, covalent binding with liver protein was delayed about 8 hr and was less than that in the group treated with urethane in water. The metabolism of urethane and production of 14CO2 from [carbonyl-14C]urethane by mouse liver homogenate in vitro were inhibited by the presence of ethanol (greater than 10 mM); these concentrations of ethanol in vitro are about the same as those that are inhibitory in vivo, but the extent of inhibition suggests that the liver is not the only site of metabolism of urethane. These results indicate that ethanol can inhibit the initial metabolism of urethane, prevent the formation of active metabolites, and allow urethane to persist in blood.

Animals↗
PubMed2005

Effect of ethanol on the tumorigenicity of urethane (ethyl carbamate) in B6C3F1 mice.

Urethane is a carcinogen to which there is widespread exposure through the consumption of fermented foods and alcoholic beverages. In this study, we have assessed the carcinogenicity of urethane in combination with ethanol. Male and female B6C3F(1) mice (48 mice per sex per group) were exposed to 0, 10, 30, or 90 ppm urethane in the presence of 0%, 2.5%, or 5% ethanol in drinking water ad libitum for two years, at which time the extent of tumorigenesis was assessed. Additional mice (four per sex per group) received the same doses for four weeks to assess serum levels of urethane and ethanol, DNA adduct formation, and the induction of microsomal cytochromes P450, cell proliferation, and apoptosis. Urethane decreased cell replication in the livers of female, but not male, mice, decreased cell replication in the lungs of both sexes, and induced cytochrome P450 2E1 in the livers of female mice. Hepatic levels of the DNA adduct 1,N(6)-ethenodeoxyadenosine were increased by exposure to urethane and decreased by treatment with ethanol. Animal weights and survival were not affected by ethanol; in contrast, urethane administration decreased body weights and survival. Urethane caused dose-dependent increases in liver, lung, and harderian gland adenoma or carcinoma and hemangiosarcoma of the liver and heart in both sexes, mammary gland and ovarian tumors in females, and squamous cell papilloma or carcinoma of the skin and forestomach in males. The increase in hepatocellular tumors occurred in a relatively linear manner and was attributed to the formation of 1,N(6)-ethenodeoxyadenosine in hepatic DNA coupled with an increase in cell replication. Hemangiosarcomas were observed only at the 90 ppm urethane dose and were probably a result of high-dose urethane-induced toxicity. Lung alveolar/bronchiolar and harderian gland adenoma or carcinoma increased in a relatively linear manner, suggestive of a genotoxic mechanism for tumor induction. Ethanol induced a dose-dependent trend in hepatocellular adenoma or carcinoma in male mice, with the incidence being marginally increased at the highest dose. In female mice administered 10 ppm and 90 ppm urethane, ethanol caused dose-related increases in alveolar/bronchiolar adenoma or carcinoma and hemangiosarcoma of the heart, respectively. This may be due to ethanol decreasing the first-pass clearance of urethane, thus, increasing systemic distribution. In male mice a different relationship was observed: ethanol caused a dose-related decrease in alveolar/bronchiolar and harderian gland adenoma or carcinoma in mice administered 30 ppm urethane.

Animals↗
PubMed1996

Co-administration of ethanol transiently inhibits urethane genotoxicity as detected by a kinetic study of micronuclei induction in mice.

Urethane (ethyl carbamate) is a genotoxic carcinogen that requires metabolic activation. Ethanol is known to inhibit urethane metabolism and genotoxicity. Since ethanol is eliminated rapidly in animals, the persistence of ethanol inhibition was studied in a mouse bone marrow and a peripheral blood micronucleus assays. In the bone marrow assay, male CD-1 mice were injected intraperitoneally (i.p.) with water (vehicle), urethane (1000 mg/kg), ethanol (2500 mg/kg) or urethane and ethanol (1000 and 2500 mg/kg, respectively) in single injections. Polychromatic erythrocytes (PCE) from bone marrow were obtained at 24 and 48 h after injection and scored for micronuclei. Urethane induced an increase of micronucleated PCE (MN PCE) frequency from 0.19% in the control to 8.63% at 24 h, followed by a decrease to 6.98% at 48 h. When urethane was co-administered with ethanol, the MN PCE frequency was suppressed to 0.49% at 24 h, but markedly increased to 7.35% at 48 h. This delay of MN PCE occurrence indicated that ethanol inhibition was transient. To pinpoint the duration of this delay, a peripheral blood micronucleus assay was conducted to monitor the kinetics of MN PCE induction. In this assay, male CD-1 mice were injected i.p. with water, ethanol, urethane, or urethane and ethanol as described above. Peripheral blood was scored for MN PCE at 8-h intervals for 4 days. Two additional dose groups injected with urethane or urethane and ethanol were also scored for MN PCE at 8 h intervals, but each blood sampling time was staggered 4 h later from the first four dose groups. The combined data provided MN PCE frequencies at 4-h intervals from 24 to 100 h after injection. Urethane alone induced a peak MN PCE frequency of 11.6% at 52 h. Urethane and ethanol induced a peak MN PCE frequency of 11.2% at 64 h, a delay of 12 h. Thus, ethanol delays but does not diminish urethane genotoxicity.

Animals↗
PubMed1995

Urethane reduces contraction to 5-hydroxytryptamine (5-HT) and enhances the action of the 5-HT antagonist ketanserin on the rat thoracic aortic ring.

The general anesthetic urethane (ethyl carbamate) is widely used in electrophysiological in vivo experiments. However, its pharmacological effects are poorly understood. Here, the effects of urethane on in vitro contractile responses of the rat thoracic aortic ring preparation were investigated. Bath application of 5-HT produced a concentration-dependent contractile response (EC50 = 4.3 x 10(-6) M). Urethane (11.2 mM = 1 mg/ml) shifted the concentration-response curve (CRC) for 5-HT to the right (EC50 = 1.7 x 10(-5) M) and decreased the maximal contraction by 30.8%. The CRC for NA (EC50 = 7.2 X 10(-9)M) was also shifted to the right by urethane (EC50 = 1.4 X 10(-8)M), but the shift of the 5-HT-CRC was twice that of the NA-CRC (3.95 vs. 1.95). The CRC to KCl was shifted rightwards only slightly by urethane (ratio 1.27) and the maximal contraction to KCl was not affected. The CRC to replacement of CaCl2 (0.1-10 mM) to KCl-depolarized vessels in a Ca(2+)-free Krebs solution was unaffected by urethane. Ketanserin (10(-9)M) antagonized the contraction to 5-HT, and a combination of ketanserin and urethane was markedly more effective than either drug alone, decreasing the maximal contraction by 58%. Antagonism of NA contraction by prazosin (5 X 10(-8)M) was not increased by addition of urethane. The urethane dose used here approximates blood and brain concentrations required to produce anesthetic effects in mammals. It is possible that reductions in 5-HT transmission and, to a lesser extent, in NA transmission, but not blockade of Ca2+ or K+ channels, may contribute to the anesthetic effect of urethane. In addition, the action of the selective 5-HT2 antagonist ketanserin is clearly altered by urethane. These findings are important to consider when urethane is used for in vivo neurophysiological investigations, particularly when 5-HT mechanisms are involved.

Adrenergic alpha-Agonists↗
PubMed1984

An analysis of the effects of urethane on cardiovascular responsiveness to catecholamines in terms of its interference with Ca++ mobilization from both intra and extracellular pools.

Urethane (1 X 10(-2) - 1 X 10(-1) M) reduced, in a concentration-dependent manner, both intra and extracellular Ca++ dependent noradrenaline-induced contractions of perfused rabbit ear artery as well as the tonic contractions produced by perfusion with high K+ solution. However, a quantitative analysis of the data indicated that for urethane concentrations similar to those found in plasma during anesthesia urethane antagonism is confined to noradrenaline-induced contractions which depend upon the mobilization of Ca++ from intracellular storage sites. In KCl-contracted arteries, urethane enhanced the relaxant effects of isoprenaline. - Urethane reduced the amplitude of contractions of spontaneously beating guinea-pig right atrium at concentrations which have only a limited effect on frequency. In addition, it decreased in a concentration-dependent manner the amplitude of isoprenaline-activated electrically driven, and K+ depolarized guinea-pig right ventricular strips. Urethane had no effect on the chrono and inotropic actions of isoprenaline on cardiac preparations. In in vivo experiments the chronotropic response to low doses of isoprenaline was significantly higher in urethane-treated as compared to unanesthetized rats. The higher dose of isoprenaline tested produced a significant fall in systolic blood pressure in urethane-anesthetized rats. A significant correlation exists between the chronotropic response to isoprenaline and resting heart rate values in urethane-anesthetized rats. These results indicate that urethane, at concentrations similar to those found in plasma during anesthesia selectively interferes with mobilization of Ca++ from intracellular storage sites. In addition, the interference of urethane anesthesia with the isoprenaline chronotropic effect 'in vivo' cannot be explained by a direct interference of urethane with beta-adrenoceptors at cardiac level.

Animals↗
PubMed1995

A pharmacokinetic study of ethanol inhibition of micronuclei induction by urethane in mouse bone marrow erythrocytes.

Urethane (ethyl carbamate) is a genotoxic carcinogen in fermented products and alcoholic beverages. The genotoxicity of urethane requires metabolic activation. Metabolism of urethane is mediated by multiple pathways, and ethanol is known to inhibit the esterase hydrolysis pathway of urethane, which accounts for over 95% of urethane metabolism. This report shows that ethanol also inhibits the induction of micronuclei by urethane in mouse bone marrow erythrocytes, presumably by inhibiting the minor pathway that generates genotoxic metabolite(s). In this study, male CD-1 mice were administered urethane, ethanol, or urethane co-administered with increasing amounts of ethanol in single intraperitoneal injections. Bone marrow polychromatic erythrocytes (PCE) obtained 24 h after injection were scored for micronuclei. The dose of urethane was 1000 mg/kg, and the doses of ethanol were 0, 625, 1250, 2000, 2250, 2500, 3000 and 3500 mg/kg. The blood ethanol level at each dose was determined. Two pharmacokinetic parameters, Cmax and AUC, were estimated for each dose. The observed Cmax of ethanol at doses of 1250, 2000, 2250, 2500, 3000 and 3500 mg/kg were 1.39, 2.84, 3.15, 3.69, 4.13 and 4.76 mg/ml, with AUCs of 1.37, 4.84, 5.88, 7.28, 10.76 and 13.51 mg.h/ml, respectively. Urethane treatment alone markedly increased the micronucleus frequency from 0.1% in the vehicle control to 2.47%. This magnitude of increase was suppressed when urethane was co-administered with ethanol at ethanol doses of 2500 mg/kg and above. At 2500, 3000 and 3500 mg/kg, the micronucleus frequencies reduced from 2.47% to 0.9, 0.44 and 0.28%, respectively. This study shows that ethanol inhibits the induction of micronuclei by urethane.

Animals↗
PubMed2005

Increased bioaccumulation of urethane in CYP2E1-/- versus CYP2E1+/+ mice.

Urethane is a fermentation by-product and a potent animal carcinogen. Human exposure to urethane occurs through consumption of alcoholic beverages and fermented foods. Recently, CYP2E1 was identified as the primary enzyme responsible for the metabolism of [(14)C]carbonyl-labeled urethane. Subsequently, attenuation of urethane-induced cell proliferation and genotoxicity in CYP2E1-/- mice was reported. The present work compares the metabolism of single versus multiple exposures of CYP2E1-/- and CYP2E1+/+ mice to (14)C-ethyl-labeled urethane. Urethane was administered as a single 10 or 100 mg/kg gavage dose or at 100 mg/kg/day for 5 consecutive days. CYP2E1+/+ mice administered single or multiple doses exhaled 78 to 88% of dose as (14)CO(2)/day. CYP2E1-/- mice eliminated 30 to 38% of a single dose as (14)CO(2) in 24 h and plateaued after day 3 at approximately 52% of dose/day. The concentrations of urethane-derived radioactivity in plasma and tissues were dose-dependent, increased as a function of the number of doses administered, and were significantly higher in CYP2E1-/- versus CYP2E1+/+ mice. Whereas urethane was the main chemical found in the plasma and tissues of CYP2E1-/- mice, it was not detectable in CYP2E1+/+ mice. In conclusion, multiple dosing led to considerable bioaccumulation of urethane in mice of both genotypes; however, greater retention occurred in CYP2E1-/- versus CYP2E1+/+ mice. Furthermore, greater bioaccumulation of (14)C-ethyl-labeled than [(14)C]carbonyl-labeled urethane was observed in mice. Comparison of the metabolism of ethyl-versus carbonyl-labeled urethane was necessary for tracing the source of CO(2) and led us to propose for the first time that C-hydroxylation is a likely pathway of urethane metabolism.

Animals↗
PubMed1996

Urethan anesthesia protects rats against lethal endotoxemia and reduces TNF-alpha release.

Urethan is a commonly used animal anesthetic for nonrecovery laboratory surgery. However, urethan has diverse biological effects that may complicate the interpretation of experimental findings. This study examined the effect of urethan on the response to an intravenous bolus of lipopolysaccharide (LPS; 30 mg/kg) in rats. In instrumented rats, urethan (1.2 gm/kg i.p.) completely prevented the fall in arterial pressure immediately after LPS administration but did not prevent late cardiovascular collapse. In uninstrumented rats, urethan also attenuated indexes of organ injury measured 4 h after LPS administration, including mural bowel hemorrhage, hemoconcentration, hypoglycemia, metabolic acidosis, and lung myeloperoxidase activity, a measure of neutrophil sequestration. The peak increase in tumor necrosis factor-alpha (TNF-alpha) 90 min after LPS administration was reduced 88% by urethan (2,060 +/- 316 vs. 16,934 +/- 847 pg/ml; P < 0.001). In uninstrumented animals, urethan at 1.2 gm/kg reduced the 90% mortality rate of a lethal dose of LPS to 0-10% when given up to 24 h before LPS administration but did not reduce mortality when given 2 h after LPS. Urethan neither directly bound LPS by Limulus assay nor inhibited LPS-stimulated TNF-alpha mRNA expression in cultured mouse peritoneal macrophages, but TNF-alpha mRNA expression was suppressed by serum from a urethan-treated rat. Moreover, rauwolscine, which shares alpha 2-adrenoceptor-blocking activity with urethan, also prevented death from a subsequent 90% lethal dose LPS bolus. We conclude that urethan or its metabolites protect against LPS, in part, by reducing TNF-alpha release and speculate that this may be mediated by alpha 2-adrenoceptors. These actions of urethan make it an undesirable anesthetic agent for in vivo studies of sepsis or LPS.

Anesthesia, General↗
PubMed1983

The kinetics of urethane elimination in the mouse.

Data from several investigators suggest that the prevalence of urethane-induced lung adenomas in the mouse is more nearly linearly related to the square of the urethane dose than to the dose itself. However, the relationship between urethane dose and integrated internal exposure to urethane has not been established. Outbred male Swiss mice between 41 and 45 days old were injected ip with one of seven doses of urethane ranging from 0.4 to 1.8 mg/g. The rate of elimination of urethane from the blood was followed by assaying the ethanol liberated from urethane by alkaline hydrolysis. The results indicated that urethane elimination is saturable, and saturated at all doses used, with a Vmax of 0.087 mg/ml/hr. Thus, internal exposure to urethane, measured as the area under the blood concentration, time curve, is not linearly related to urethane dose. In the range of doses used in this study, the area under the curve is C0(2)/2Vmax or (D/VD)2 (1/2Vmax), where C0 is the initial concentration; D, the dose; and VD, the volume of distribution. This relationship can be used to predict internal exposure to urethane as a function of dose.

Animals↗
PubMed1991

The role of metallothionein induction and altered zinc status in maternally mediated developmental toxicity: comparison of the effects of urethane and styrene in rats.

We hypothesize that maternal metallothionein (MT) induction by toxic dosages of chemicals may contribute to or cause developmental toxicity by a chain of events leading to a transient but developmentally adverse decrease in Zn availability to the embryo. This hypothesis was tested by evaluating hepatic MT induction, maternal and embryonic Zn status, and developmental toxicity after exposure to urethane, a developmental toxicant, or styrene, which is not a developmental toxicant. Pregnant Sprague-Dawley rats were given 0 or 1 g/kg urethane ip, or 0 or 300 mg/kg styrene in corn oil po, on Gestation Day 11 (sperm positive = Gestation Day 0). These were maternally toxic dosages. As both treatments decreased food consumption, separate pair-fed control groups were also evaluated for effects on MT and Zn status and development. In addition, Gestation Day 11 rat embryos were exposed to urethane in vitro in order to determine whether urethane has the potential to be directly embryotoxic. Urethane treatment induced hepatic MT 14-fold over control; styrene treatment induced MT 2.5-fold. The MT induction by styrene could be attributed to decreased food intake, as a similar level of induction was observed in a pair-fed untreated control group. However, the level of MT induction by urethane was much greater than that produced by decreased food intake alone. Hepatic Zn concentration, particularly in the cytosol, was increased in the presence of increased hepatic MT concentration. Plasma Zn concentration was significantly decreased (approximately 30%) by urethane treatment, but not by styrene or food restriction (pair-feeding). Distribution of 65Zn to the liver of urethane-treated dams was significantly greater (by 30%), while distribution to embryonic tissues was significantly lower (by at least 50%) than in pair-fed or ad lib.-fed controls. Styrene treatment had no effect on 65Zn distribution. Urethane was developmentally toxic, causing an 18% decrease in fetal weight and a significant delay in skeletal ossification, but was not toxic to rat embryos in vitro. Styrene was not developmentally toxic. The changes observed after urethane treatment, namely substantial hepatic MT induction and altered maternal and embryonic Zn status, along with the lack of direct embryotoxicity of urethane in vitro, support the hypothesis that these maternal effects contribute to developmental toxicity. The lack of similar changes in styrene-intoxicated dams provides one explanation for its low developmental toxicity at maternally toxic dosages.

Abnormalities, Drug-Induced↗
PubMed2002

The anesthetic mechanism of urethane: the effects on neurotransmitter-gated ion channels.

UNLABELLED: Urethane is widely used as an anesthetic for animal studies because of its minimal effects on cardiovascular and respiratory systems and maintenance of spinal reflexes. Despite its usefulness in animal research, there are no reports concerning its molecular actions. We designed this study to determine whether urethane affects neurotransmitter-gated ion channels. We examined the effects of urethane on recombinant gamma-aminobutyric acid(A), glycine, N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. Urethane potentiated the functions of neuronal nicotinic acetylcholine, gamma-aminobutyric acid(A), and glycine receptors, and it inhibited N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in a concentration-dependent manner. At concentrations close to anesthetic 50% effective concentration, urethane had modest effects on all channels tested, suggesting the lack of a single predominant target for its action. This may account for its usefulness as a veterinary anesthetic. However, a large concentration of urethane exerts marked effects on all channels. These findings not only give insight into the molecular mechanism of anesthetics but also caution that neurophysiologic measurements from animals anesthetized with urethane may be complicated by the effects of urethane on multiple neurotransmitter systems. Our results also suggest that small changes in multiple receptor systems can produce anesthesia. IMPLICATIONS: Urethane modestly affects multiple neurotransmitter systems at an anesthetic concentration. Our findings suggest that these degenerate effects of urethane can produce anesthesia and that urethane has a potential to influence neuronal measurements made in in vivo preparations.

Anesthetics, Intravenous↗
PubMed2001

In vitro studies on the effect of physical cross-linking on the biological performance of aliphatic poly(urethane urea) for blood contact applications.

The effect of physical cross-linking in candidate cycloaliphatic and hydrophobic poly(urethane urea) (4,4'-methylenebis(cyclohexylisocyanate), H(12)MDI/hydroxy-terminated polybutadiene, HTPBD/hexamethylenediamine, HDA) and poly(ether urethane urea)s (H(12)MDI/HTPBD-PTMG/HDA) on the in vitro calcification and blood-material interaction was studied. All the candidate poly(urethane urea)s and poly(ether urethane urea)s elicit acceptable hemolytic activity, cytocompatibility, calcification, and blood compatibility in vitro. The studies on blood-material interaction reveal that the present poly(urethane urea)s are superior to polystyrene microtiter plates which were used for the studies on blood-material interaction. The present investigation reveals the influence of physical cross-link density on biological interaction differently with poly(urethane urea) and poly(ether urethane urea)s. The higher the physical cross-link density in the poly(urethane urea)s, the higher the calcification and consumption of WBC in whole blood. On the other hand, the higher the physical cross-link density in the poly(ether urethane urea)s, the lesser the calcification and consumption of WBC in whole blood. However a reverse of the above trend has been observed with the platelet consumption in the poly(urethane urea)s and poly(ether urethane urea)s.

Animals↗
PubMed1984

Consideration of the mechanism of pulmonary adenogenesis in urethane-treated Swiss mice.

A number of investigators have observed a quadratic relationship between acute urethane dose and cumulative pulmonary adenoma incidence in mice. The hypothesis was tested that this dose-effect relationship may be explained by consideration of the elimination kinetics of urethane. Single doses of 0.4 to 1.8 mg urethane per g body weight were given ip to 6-week-old Swiss-Cox mice. The measure of internal exposure to the intact urethane molecule for a given external urethane dose was taken to be the area under the curve (AUC alpha) of a blood urethane concentration versus time plot. AUC alpha was linearly related to tumor prevalence. When urethane elimination was induced by pretreatment of the mice with p,p'-DDT, the linear relationship of AUC alpha to tumor prevalence was shifted. Reduction of tumor prevalence by p,p'-DDT pretreatment was more marked than that predicted on the basis of exposure to urethane. Thus, the kinetic evidence is consistent with biochemical evidence from other investigators supporting the premise that activation of urethane to a reactive metabolite is required for adenoma formation in the mouse lung. While exposure to the adenogenic moiety is evidently closely proportional to internal exposure to urethane in both pretreated and non-pretreated mice, p,p'-DDT pretreatment causes a shift in this proportionality.

Adenoma↗
PubMed1984

Urethan (ethyl carbamate) alone is carcinogenic for mouse skin.

Nine groups of 32 hairless mice (16 males and 16 females in each) were painted on the back skin with approximately 200 microliters solution of urethan twice a week for up to 58 weeks. The following treatments were given: acetone alone, propylene glycol alone, 10% urethan in acetone, 15% urethan in propylene glycol, 20% urethan in acetone, 30% urethan in propylene glycol, 40% urethan in acetone, 75% urethan in propylene glycol, and approximately 100% melted urethan. Histological examinations revealed no development of general epidermal hyperplasia or inflammatory reactions. Tumors developed in skin, liver and lymph nodes, and one mouse also developed leukemic infiltrations in kidneys and lungs. The rate and yield of skin tumors were registered and statistically analyzed. The number of other tumors occurring was also recorded. The results confirm that urethan is a tumorigen for the lung and several other organs, and that it is also a complete carcinogen for hairless mouse skin, even in a dose as low as 10% urethan in acetone. There is also a significant dose-response relationship.

Animals↗
PubMed2006

Inhibition of urethane-induced carcinogenicity in cyp2e1-/- in comparison to cyp2e1+/+ mice.

Urethane is an established animal carcinogen and has been classified as "reasonably anticipated to be a human carcinogen." Until recently, urethane metabolism via esterase was considered the main metabolic pathway of this chemical. However, recent studies in this laboratory showed that CYP2E1, and not esterase, is the primary enzyme responsible for urethane oxidation. Subsequent studies demonstrated significant inhibition of urethane-induced genotoxicity and cell proliferation in Cyp2e1-/- compared to Cyp2e1+/+ mice. Using Cyp2e1-/- mice, current studies were undertaken to assess the relationships between urethane metabolism and carcinogenicity. Urethane was administered via gavage at 1, 10, or 100 mg/kg/day, 5 days/week, for 6 weeks. Animals were kept without chemical administration for 7 months after which they were euthanized, and urethane carcinogenicity was assessed. Microscopic examination showed a significant reduction in the incidences of liver hemangiomas and hemangiosarcomas in Cyp2e1-/- compared to Cyp2e+/+ mice. Lung nodules increased in a dose-dependent manner and were less prevalent in Cyp2e1-/- compared to Cyp2e+/+ mice. Microscopic alterations included bronchoalveolar adenomas, and in one Cyp2e1+/+ mouse treated with 100 mg/kg urethane, a bronchoalveolar carcinoma was diagnosed. Significant reduction in the incidence of adenomas and the number of adenomas/lung were observed in Cyp2e1-/- compared to Cyp2e1+/+ mice. In the Harderian gland, the incidences of hyperplasia and adenomas were significantly lower in Cyp2e1-/- compared to Cyp2e+/+ mice at the 10 mg/kg dose, with no significant differences observed at the high or low doses. In conclusion, this work demonstrated a significant reduction of urethane-induced carcinogenicity in Cyp2e1-/- compared to Cyp2e1+/+ mice and proved that CYP2E1-mediated oxidation plays an essential role in urethane-induced carcinogenicity.

Animals↗
PubMed1990

Carcinogenicity of sublimed urethane in mice through the respiratory tract.

The carcinogenicity of sublimed urethane (ethyl carbamate) in air was examined with mice. JCL:ICR mice were nursed in a plastic cage inside a vinyl chamber which was ventilated 4 times per hour. The mice were exposed to urethane gas for various periods by passing air which contained a high concentration of sublimed urethane (1.29 micrograms/ml) into the vinyl chamber, or by placing a vessel containing crystalline urethane inside the vinyl chamber so that it was filled with spontaneously-sublimed urethane gas at a low concentration (0.25 microgram/ml). When female mice were killed 5 months after exposure, lung tumor frequency increased almost linearly with the number of days of exposure in the low concentration experiment, but increased in a non-linear manner in the high concentration experiment. In terms of nearly the same total dose, i.e., (concentration of urethane gas in air) X (days of inhalation), one day of exposure to urethane gas at the low concentration induced lung tumors at a significantly higher frequency than 1/4 day of exposure to urethane gas at the high concentration. When male mice were killed at 12 months after exposure to examine the progressive change of induced tumors, malignant, invasive and metastatic tumors were found to have been induced more frequently in the lung after exposure to urethane gas at the low concentration (0.25 microgram/ml for 10 days) than at the high concentration (1.29 microgram/ml for 4 days), although the total dose in the former group was about half of that in the latter. Continuous exposure to urethane gas for a longer period at the low concentration seems to be more efficient for the induction, promotion and/or progression of lung tumors than the exposure for a shorter period at the high concentration.

Administration, Inhalation↗
PubMed1994

Crystal structure and NMR conformation of a cyclic pseudotetrapeptide containing urethane backbone linkages.

Urethane bonds, derived from the hydroxyl group of the tyrosine side chain, have been investigated as a new type of amide bond mimetic in the design of pseudopeptides. The structure of a representative cyclic pseudotetrapeptide that consists of an -Ala-Tyr(urethane)Ala-Tyr(urethane) sequence fused into a rigid ring has been studied in the solid state by x-ray crystallography and in solution by two-dimensional nmr techniques. The cyclic pseudotetrapeptide has an oblong shape. The backbone urethane bonds assume a trans-trans conformation. The carbonyl groups in the ring have an alternating pattern of down, up, down, up with respect to the average ring plane. Solution nmr studies give observed nuclear Overhauser effects and coupling constants largely in agreement with the crystal structure. However, in solution the observed structure is likely to be conformationally averaged, and in the averaged structure, the urethane bond is perpendicular to the plane of the aromatic ring of the tyrosine, while in the crystal it is close to this plane. These differences may be explained by intermolecular hydrogen-bonding interactions. Four aspects of the conformation of the cyclic pseudotetrapeptide were investigated in detail: the tyrosine residue with the attached side-chain urethane bond (the tyrosine-urethane unit), the conformation of the two urethane backbone linkages, the conformation of the two conventional peptide bonds within this unusual ring structure, and the tight turns within the cyclic pseudotetrapeptide. The conformation of the tight turns present in the cyclic pseudotetrapeptide is very similar to that of a beta-bend of type II. Intermolecular hydrogen bonding, joining adjacent layers of the cyclic pseudotetrapeptide in the solid state, resemble a parallel beta-pleated sheet. The presence of these structural motifs in the cyclic pseudotetrapeptide indicates that the tyrosine urethane unit may find applications in peptide and protein engineering.

Amino Acid Sequence↗