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PubMed2001

Telomerase activation and p53 mutations in urethane-induced A/J mouse lung tumor development.

The mouse telomerase holoenzyme, which synthesizes telomeric DNA de novo, is a ribonucleoprotein complex that includes the mouse telomerase RNA component (mTERC), mouse telomerase-associated protein (mTEP1) and mouse telomerase reverse transcriptase (mTERT). To determine the role of telomerase in urethane-induced lung tumorigenesis in A/J mice we examined telomerase activity and the expression of each telomerase subunit in 20 tumor samples, harvested at 16, 28, 40 and 50 weeks after urethane treatment. The telomeric repeat amplification protocol assay showed that statistically significant telomerase activation occurred both early and late in tumorigenesis. Semi-quantitative reverse transcription-polymerase chain reaction analysis revealed that mRNA expression levels of mTEP1 and mTERT were up-regulated during tumor progression, while mTERC expression was not significantly different between tumors and normal lung. We further examined mTEP1 protein expression in normal lung tissue and lung tumors; western blot analysis showed preferential expression of mTEP1 protein in lung tumors compared with normal lung and immunohistochemistry revealed that a majority of the adenoma cells were positively stained in the nucleus, whereas only a few of the adjacent normal alveolar cells were immunoreactive. In addition, we investigated DNAs of the 20 tumor samples by single strand conformation polymorphism and sequencing analyses to examine whether alterations of the p53 gene in exons 5-8 were associated with telomerase activity. Although we found one nonsense, two missense, two silent and one simultaneous double mutation at different codons in six late stage tumors, there was no apparent correlation between telomerase activity and p53 mutations. Collectively, these results suggest that mTEP1 as well as mTERT may be involved in the regulation of telomerase activity and that telomerase activation may contribute to lung tumorigenesis in A/J mice independently of p53 gene alterations.

Animals↗

PubMed2004

Increased susceptibility to urethane-induced lung tumors in mice with decreased expression of connexin43.

Gap junction intercellular communication capacity and connexin expression are reportedly decreased in human lung cancer. The mechanisms by which connexins, the gap junction proteins, act as tumor suppressors are unclear. In order to understand the involvement of connexins in tumorigenesis, we analyzed the effect of the heterologous deletion of Gja1 [the connexin43 (Cx43) gene] on the development of lung adenomas in mice. Heterozygous (Cx43(+/-)) and wild-type mice (Cx43(+/+)) were treated or not with single doses of urethane at 15 and 17 days after birth. Twenty-five weeks later, both the number and size of nodules were increased in Cx43(+/-) mice as compared with Cx43(+/+) mice. Moreover, the lesions were histologically more aggressive in the heterozygous mice. However, no increase in spontaneous lesions was observed in the lungs of untreated Cx43(+/-) mice. Heterozygous mice effectively presented lower expression of Cx43 genes and decreased amounts of Cx43. In conclusion, our results indicate that deletion of one allele of the Cx43 gene clearly favors the carcinogenic effect of urethane administration and results in a higher susceptibility to lung adenoma formation in mice.

Adenoma↗

PubMed2002

The single laser flow cytometric micronucleus test: a time course study using colchicine and urethane in rat and mouse peripheral blood and acetaldehyde in rat peripheral blood.

A single laser flow cytometric procedure to quantify micronucleus frequency in rat and mouse peripheral blood was evaluated. Reticulocytes express the transferrin receptor (also known as the CD71-defined antigen). When combined with a DNA stain, antibodies against this antigen can be used to differentially label and quantify micronucleated reticulocytes. The object of this study was to evaluate the method for rat and mouse peripheral blood using flow cytometry and compare the results obtained between two laboratories (GlaxoWellcome and Litron Laboratories). The compounds selected were the rodent carcinogens colchicine, urethane and acetaldehyde. Colchicine gives a positive response in the rat bone marrow micronucleus assay and an inconclusive result in the rat peripheral blood micronucleus assay. The latter two are both established rat carcinogens readily detected in both the bone marrow and peripheral blood micronucleus assays. In these experiments both rat and mice were treated with either colchicine or urethane and rats alone treated with acetaldehyde. After a single treatment, repeat sampling of peripheral blood was made at 0, 24, 48 and 72 h. Replicate blood samples were obtained and fixed for flow cytometric analysis at both facilities. The micronucleated reticulocyte frequency of each blood sample was determined by analysing 20 000 total reticulocytes per blood sample. The data suggest that the single laser flow cytometric procedure resulted in consistent reticulocyte and micronucleated reticulocyte frequencies between laboratories. Furthermore, these flow cytometric data compare favourably with previously published data.

Acetaldehyde↗

PubMed2005

Carbachol injections into the ventral pontine reticular formation activate locus coeruleus cells in urethane-anesthetized rats.

STUDY OBJECTIVES: Two pontine reticular regions are implicated in cholinergic triggering of rapid eye movement (REM) sleep: the dorsomedial tegmental region and the ventral nucleus pontis oralis. We previously determined that, in urethane-anesthetized rats, microinjections of a cholinergic agonist, carbachol, into the dorsal region produce REM sleep-like effects comprising cortical activation, hippocampal theta rhythm, suppression of hypoglossal (XII) nerve activity, and silencing of pontine noradrenergic neurons. Our goal was to determine whether carbachol injections into the ventral nucleus pontis oralis elicits comparable effects. DESIGN: Recording of cortical electroencephalogram, hippocampal activity, XII nerve activity, and discharge of noradrenergic cells of the locus coeruleus. SETTING: Basic neurophysiologic research laboratory. PARTICIPANTS AND INTERVENTIONS: Urethane-anesthetized, paralyzed, and artificially ventilated or nonparalyzed and spontaneously breathing rats with microinjections of carbachol (10 nL, 10 mM) into the ventral nucleus pontis oralis. MEASUREMENTS AND RESULTS: In artificially ventilated rats, carbachol injections repeatedly elicited cortical activation and hippocampal theta rhythm. Concomitantly, the activity of locus coeruleus neurons increased from 2.0 per second +/- 0.4 (SE) to 2.6 per second +/- 0.4 (P < .05, n = 8), as did XII nerve activity (by 42.5% +/- 8.8%; P < .01). In spontaneously breathing animals, carbachol similarly activated the cortical electroencephalogram and hippocampal activity, whereas XII nerve activity was reduced by 6.7% +/- 2.5% (P < .05) together with increased ventilation, as indicated by reduced end-expiratory CO2. CONCLUSION: Carbachol injections into the ventral nucleus pontis oralis activate, rather than silence, noradrenergic locus coeruleus neurons. This is not compatible with the state of REM sleep.

Anesthetics, Intravenous↗

PubMed1993

Liver disease from surreptitious administration of urethane.

We report subacute necrosis, peliosis hepatis, venoocclusive disease and hepatic angiosarcoma after long-term administration of urethane. We take this to be the 12th case of urethane-induced hepatitis and the first associated with vascular liver tumor.

Chronic Disease↗

PubMed1991

Quantitative risk assessment of carcinogenicity of urethane (ethyl carbamate) on the basis of long-term oral administration to B6C3F1 mice.

A carcinogenicity study of urethane was performed for quantitative assessment of its risk in humans. Three hundred 6-week-old male B6C3F1 mice were divided into 6 groups, each consisting of 50 mice, and urethane was given ad libitum in drinking water at levels of 0 (control), 0.6, 3, 6, 60 and 600 ppm for 70 weeks. The tumors with a clear dose-response relationship were lung tumor (alveolar/bronchiolar adenoma or carcinoma) and liver tumor (hemangioma or angiosarcoma). The incidences of these two types of tumor were applied to estimation of the virtually safe dose (VSD) at the level of 10(-6) by using four mathematical models (Logit, Probit, Weibull and Multistage models). The VSD based on the incidences of lung tumor by using the Logit model was estimated to be 1.8 x 10(-4) mg/kg body weight/day. On the other hand the VSD based on those of liver tumor by using the Weibull model was 7.2 x 10(-5) mg/kg body weight/day. Thus, the VSDs based on the incidences of the two different types of tumor using the most compatible mathematical model in each case, as judged from the P-values, were similar.

Adenoma↗

PubMed1995

Role of point mutation of the K-ras gene in tumorigenesis of B6C3F1 mouse lung lesions induced by urethane.

In order to elucidate the role of point mutation of the K-ras gene in the tumorigenetic process of lung tumors, an experimental model of lung lesions in mice induced by the administration of urethane was used. A total of 135 B6C3F1 male mice, 6 weeks old, were given urethane in the drinking water at 0, 6, 60, 600 or 1200 ppm, and were then killed after varying periods of time. The lung lesions were histologically characterized as hyperplasia, adenoma and adenocarcinoma. Point mutations in codons 12 and 61 of the K-ras gene were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by using dideoxy sequencing analysis. K-ras gene mutation was identified in 9 (23.7%) of 38 lesions classified as hyperplasia, 31 (46.3%) of 67 adenomas, and 3 (50%) of 6 adenocarcinomas. The most frequent mutation was an AT-to-TA transversion at the second base of codon 61 and this pattern accounted for 65% of the three mutant forms observed. These results suggest that the point mutation of K-ras gene is involved in all stages of mouse lung tumorigenesis, i.e., activation of this gene can also influence the later stages of lung lesions.

Adenocarcinoma↗

PubMed1976

Autoradiographic study of type II-cell hyperplasia in lungs of mice chronicall exposed to urethane.

Hyperplasia of pulmonary alveolar epithelium was induced by exposure of adult mice to 0-1% urethane in drinking water, and their lungs were analysed using combined autoradiographic and morphometric methods. The response of pulmonary epithelium showed three phases: an initial one of 3 weeks in which the number of type II cells was consistently low and, after a transient decrease in 3H-thymidine labeling index, the latter steadily increased. Degenerating or dead type II cells were found, consequently this period was considered one in which cell death was disproportionately increased over cell production. Between the 3rd and 6th weeks the number of type II cells doubled, and thereafter increased at a slower rate. The 3H-thymidine labeling index reached its peak at 6 weeks. The third phase was marked by a decline in labeling index which returned to near-normal levels by the 16th week. The number of type II cells declined slowly after the 10th week and was still elevated at the end of the observation period. Tumors consisting of type II cells continued to arise even during the period of declining labeling index. The dissociation between the proliferative response which was reversible, and the neoplastic response which was not, supports the assumption that the major part of the observed population growth or hyperplasia induced by urethane was a form of regeneration repair secondary to cell death and may be unrelated to tumor growth.

Animals↗

PubMed1988

Synthesis and translocation of gangliosides and glycoproteins during urethane anesthesia.

In this work, we have studied (a) the contents of gangliosides, glycoproteins, and phospholipids of the vesicle and plasma membrane fractions from brains of anesthetized and control rats and chickens and (b) the labeling of gangliosides and glycoproteins in the retina ganglion cell layer and optic tectum of urethane-anesthetized and control chickens after intraocular injection of a labeled N-acetylneuraminic acid precursor and the distribution of the label after subcellular fractionation. We found an increase in the content of gangliosides relative to protein in the vesicle fraction of both anesthetized rats and chickens relative to their controls. Other values were not affected by anesthesia. These results do not reflect a faster synthesis of gangliosides stimulated by urethane, because their rate of labeling was diminished in anesthetized animals. During the 4-h period after the animals were injected intraocularly with the radioactive precursor, the highest values of ganglioside-specific radioactivity were found in the vesicle fraction of control and anesthetized animals; at longer intervals, the specific radioactivity of the vesicle and plasma membrane fractions became rather similar. These data are in accordance with previous studies from this laboratory suggesting that the synthesis of the carbohydrate chain of gangliosides is regulated by the physiological demands made by the neurotransmitting system.

Anesthesia↗

PubMed1980

Pressure reversal of the effect of urethane on the evoked somatosensory cortical response in the rat.

1 The cerebral response evoked by stimulation of the forepaw in the rat shows an increase in latency and decrease in the amplitude of its initial components as anaesthetic dose (urethane) is increased. 2 These changes are reversed if the ambient pressure is increased with helium and the electrocorticogram shows an increase in basic frequency. 3 The dose of urethane needed to prevent reflex response to tail stimulation is increased as pressure increases. 4. The implications of these behavioural and somatosensory responsiveness changes as pressure is increased are discussed.

Animals↗

PubMed1983

Etomidate-anaesthesia, with and without fentanyl, compared with urethane-anaesthesia in the rat.

In spontaneously breathing rats, continuous infusion of etomidate with and without fentanyl caused a slight decrease in blood pressure and heart rate. Coadministration of fentanyl and etomidate in order to obtain full anaesthesia and analgesia resulted in respiratory depression. In artificially ventilated rats both etomidate as well as the anaesthetic combination caused a strong reduction in aortic flow and an increase in total peripheral resistance. A single infusion of etomidate did not change blood pressure. Etomidate combined with fentanyl reduced blood pressure. Under adjusted ventilation blood pressure, aortic flow, max(dF/dt) and heart rate were progressively reduced during a 4 h period. In contrast, urethane anaesthesia reduced aortic flow to a minor extent. Total peripheral resistance and max(dF/dt) were hardly affected. The slightly reduced blood pressure and blood gas variables remained stable during the experiment. From pharmacokinetic studies it was established that effective etomidate plasma levels were maintained constant during the experimental period. Pharmacokinetic interaction between etomidate and fentanyl did not occur. It is concluded that for anaesthesia of longer duration during cardiovascular experiments in rats, urethane is preferable to etomidate/fentanyl because it does not cause serious changes in basal haemodynamic variables.

Anesthesia↗

PubMed1997

Mechanistic modeling of multiple tumorigenesis: an application to data on lung tumors in mice exposed to urethane.

This paper discusses an application of the stochastic model of carcinogenesis proposed by Yakovlev and Polig to the analysis of experimental data on multiple pulmonary tumors induced by urethane. The results of this analysis suggest that the rate of administration of urethane has no effect on the mean number of initiated cells per unit dose. Likewise, the formation of lesions responsible for cell death appears to be unaffected by the dose rate.

Adenoma↗

PubMed1990

Effects of clenbuterol treatment on the responses to vasodilators in urethane-anaesthetized rats.

Seven or 14 days of treatment with the beta 2-adrenoceptor agonist clenbuterol, 0.3 mg kg-1, s.c., twice daily, increased the basal mean blood pressure in normotensive urethane-anaesthetized rats. The elevated pressure values were maintained until 48 h after the end of the 14 day treatment. Clenbuterol treatment decreased the vasodilatory responses to the beta-adrenoceptor agonist isoprenaline and adenosine, agents which act through an increase in intracellular cyclic AMP. Decreased responses were maintained until 48 h after a 14 day treatment with clenbuterol. On the other hand, its administration to rats for 14 days did not modify the vasodilator responses to acetylcholine or sodium nitroprusside, two agents that exert their effects by enhancing cyclic GMP. The increase in mean blood pressure in urethane-anaesthetized rats after clenbuterol treatment may be a consequence of a reduced vasodilator beta 2-adrenoceptor-mediated response to circulating catecholamines.

Acetylcholine↗

PubMed1988

Effects of urethane, ambient temperature and injection route on rat body temperature and metabolism due to endotoxins.

1. We have investigated the influence of environmental temperature, anaesthesia and route of administration on rectal temperature and other metabolic responses to two preparations of bacterial endotoxin in male adult Wistar rats. 2. Urethane anaesthesia, environmental temperatures of 20 and 28 degrees C, subcutaneous (S.C.) and intraperitoneal (I.P.) routes of administration and butanol and trichloroacetic acid (TCA) extracts of E. coli endotoxin (1.2 mg/kg) were used. 3. In addition to rectal temperature, serum zinc, albumin and urea concentrations and liver protein, RNA and zinc contents were measured. 4. Fevers were produced by injections of both endotoxins, by either route at 28 degrees C. Butanol-extracted endotoxin produced a more rapid response than the TCA extract via the I.P. route whereas the TCA extract produced a higher temperature than the butanol extract when the S.C. route was used. 5. Fevers were inhibited at an environmental temperature of 20 degrees C and by anaesthesia, while the former had no effect on compositional changes the latter inhibited the fall in serum zinc in response to subcutaneous doses of either endotoxin and the increase in liver zinc content in response to the butanol extract of endotoxin. 6. At 20 degrees C a marked fall in rectal temperature occurred in conscious rats 2 h after receiving the TCA but not the butanol extract of endotoxin. Temperature depression was more severe when endotoxin was administered by the I.P. route. 7. Serum urea was elevated in conscious rats by the TCA extract of endotoxin via both routes but only by the I.P. route for the butanol extract of endotoxin. In anaesthetized animals only the TCA extract of endotoxin raised serum urea concentration when given intraperitoneally. 8. Serum albumin and liver protein and RNA were unaffected by endotoxin injections over the 7 h time course of the study. 9. Rectal temperature responses to endotoxins were influenced in direction and magnitude by all variables employed in the study, while compositional changes were unaffected by environmental temperature but influenced to varying degrees by urethane anaesthesia and the route of administration employed.

Anesthesia↗

PubMed1962

Homograft reaction in mice: effect of urethane and sublethal x-radiation.

Combined treatment of mice with urethane (a nucleic acid antagonist and mitotic inhibitor) plus sublethal x-radiation (500 rad) suppresses the homograft response to a degree considerably greater than that observed with this dose of x-rays alone. Thus, LAF(1) mice receiving two injections of urethane plus 500 rad of x-radiation prior to grafting retained C(3)H mouse skin grafts for periods up to 60 days, with a mean graft survival time of 40 days, as compared with 18 days for mice exposed to 500 rad only.

Allografts↗

PubMed1971

Diethyl pyrocarbonate: formation of urethan in treated beverages.

Isotope dilution analyses with tritium-labeled diethyl pyrocarbonate show that the carcinogen urethan is formed in orange juice, white wine, and beer. Commercial use of the antimicrobial food additive diethyl pyrocarbonate can result in urethan concentrations of 0.1 to 0.2 milligram per liter in orange juice and of the order of 1 milligram per liter in white wine and beer.

Ammonia↗

PubMed1979

Induction of mouse mammary tumor virus RNA in mammary tumors of BALB/c mice treated with urethane, X-irradiation, and hormones.

The involvement of mouse mammary tumor virus (MTV) in the development of mammary tumors of nonviral etiology in BALB/c mice was studied by measuring the levels of MTV RNA, MTV DNA, and MTV proteins in spontaneously arising and hormonally, chemically, and/or physically induced mammary tumors of BALB/c females. The following results were obtained. (i) Spontaneous mammary tumors contained very low levels of MTV RNA; 4 X 10(-6)% of the the cytoplasmic RNA was MTV RNA. No MTV proteins could be demonstrated by using sensitive radioimmunoassays for MTV proteins p27 and gp52. (ii) Mammary tumors induced by treatments with urethane or X-irradiation alone contained higher levels of MTV RNA; these tumors contained 3- and 19-fold more MTV RNA, respectively, compared with spontaneous mammary tumors. (iii) Mammary tumors induced by combined treatment with urethane and X-irradiation expressed high levels of MTV RNA in the mammary tumors; a 1,724-fold increase in MTV RNA content compared with spontaneous mammary tumors was observed. However, very low levels of MTV proteins gp52 and p27 were detected, suggesting some kind of impairment at the translation of the MTV RNA. MTV RNA was also induced by this treatment in mammary glands and spleens, but not in the livers of tumor-bearing animals. (iv) Balb/c females continuously exposed to prolactin contained high levels of MTV RNA and MTV proteins in stimulated mammary glands and in the hormonally induced mammary tumors. These findings suggest that MTV is not responsible for the maintenance and probably also not for the development of all murine mammary cancers.

Animals↗

PubMed2004

Dose-dependent effects of L-carnosine on the renal sympathetic nerve and blood pressure in urethane-anesthetized rats.

The physiological function of L-carnosine (beta-alanyl-L-histidine) synthesized in mammalian muscles has been unclear. Previously, we observed that intravenous (i.v.) injection of L-carnosine suppressed renal sympathetic nerve activity (RSNA) in urethane-anesthetized rats, and L-carnosine administered via the diet inhibited the elevation of blood pressure (BP) in deoxycorticosterone acetate salt hypertensive rats. To identify the mechanism, we examined effects of i.v. or intralateral cerebral ventricular (l.c.v.) injection of various doses of L-carnosine on RSNA and BP in urethane-anesthetized rats. Lower doses (1 microg i.v.; 0.01 microg l.c.v.) of L-carnosine significantly suppressed RSNA and BP, whereas higher doses (100 microg i.v.; 10 microg l.c.v.) elevated RSNA and BP. Furthermore, we examined effects of antagonists of histaminergic (H1 and H3) receptors on L-carnosine-induced effects. When peripherally and centrally given, thioperamide, an H3 receptor antagonist, blocked RSNA and BP decreases induced by the lower doses of peripheral L-carnosine, whereas diphenhydramine, an H1 receptor antagonist, inhibited increases induced by the higher doses of peripheral L-carnosine. Moreover, bilateral lesions of the hypothalamic suprachiasmatic nucleus eliminated both effects on RSNA and BP induced by the lower (1 microg) and higher (100 microg) doses of peripheral L-carnosine. These findings suggest that low-dose L-carnosine suppresses and high-dose L-carnosine stimulates RSNA and BP, that the suprachiasmatic nucleus and histaminergic nerve are involved in the activities, and that L-carnosine acts in the brain and possibly other organs.

Anesthetics, General↗