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Biomedical subjects

W Lijinsky

Publications and source records attributed to W Lijinsky.

At least 91 records · Page 5Linked to original sources
PubMed1986

Rat and mouse forestomach tumors induced by chronic oral administration of styrene oxide.

Styrene oxide (CAS: 96-09-3) was administered in corn oil by gavage three times a week at two dose levels to groups of 52 male and 52 female F344 rats and 52 male and 52 female B6C3F1 mice for 2 years, after which the surviving animals were killed and examined histopathologically. The doses given to rats were 550 and 275 mg/kg (body wt) per treatment; in mice the two doses were 750 and 375 mg/kg (body wt) per treatment. The main pathologic findings were high incidences of squamous cell carcinomas or papillomas of the forestomach in both sexes of both rats and mice. These neoplasms were virtually absent from the 52 controls of either sex of both species given parallel treatment with corn oil alone. There was a statistically significant increase in the incidence of hepatocellular neoplasms in male mice receiving 375 mg styrene oxide/kg. Styrene oxide is carcinogenic to both sexes of F344 rats and B6C3F1 mice when administered orally in corn oil.

Administration, Oral↗
PubMed1986

Chronic toxicity study of cyclohexanone in rats and mice.

A 2-year chronic toxicity assay of cyclohexanone (CAS: 108-94-1) was conducted in F344 rats and (C57BL/6 X C3H)F1 mice by administering a solution of cyclohexanone in drinking water. Two concentrations were given to rats, 6,500 and 3,300 ppm (wt/vol). Male mice received 13,000 and 6,500 ppm, while female mice were given three concentrations, 25,000, 13,000, and 6,500 ppm. Each treatment group consisted of 50 or 52 male and 50 or 52 female rats or mice, except 47 male mice treated with the highest dose and 41 female mice treated with the highest dose, and there was a group of untreated controls of each species. Survival and weight gain were similar to those of controls at the lowest cyclohexanone dose in both sexes of both species, but weight gain was depressed at all of the higher doses. Survival was good (greater than 80% at 90 wk) in all groups except in female mice at the 2 highest doses; at 25,000 ppm of cyclohexanone, only 50% of mice lived beyond 1 year. Most of the neoplasms in the treated groups did not differ significantly in number from those in the controls. Male rats receiving 3,300 ppm cyclohexanone had a 13% incidence of adrenal cortex adenomas (7 animals) compared with an incidence of 2% in controls; the incidence of this neoplasm did not increase in the male rats receiving 6,500 ppm or in the female rats given either dose. The mice had a statistically significant increase in incidence of lymphomas-leukemias among the females given 6,500 ppm, but not among the groups given higher doses of cyclohexanone. Male mice given 6,500 ppm cyclohexanone showed an increased incidence of hepatocellular adenomas and carcinomas, 50% versus 32.5% in controls, but the incidence of these neoplasms was only 37% in the male mice given 13,000 ppm cyclohexanone. The incidence of lymphomas in male mice and of hepatocellular neoplasms in female mice given cyclohexanone did not differ from that in the controls. The evidence for carcinogenic activity of cyclohexanone is marginal and the effect, if any, is weak.

Adenoma↗
PubMed1986

Methylation versus ethylation of DNA in target and nontarget tissues of Fischer 344 rats treated with N-nitrosomethylethylamine.

Bioactivation of N-nitrosomethylethylamine can be initiated by hydroxylation of either the methyl or ethyl moiety leading to an ethylating or methylating intermediate, respectively. This study was designed to determine which of these metabolic pathways predominates in vivo and to what extent DNA is alkylated in the target and nontarget tissues. Adult male Fischer 344 rats received a single i.p. or p.o. dose (4.4 mg/kg, 0.05 mmol/kg) of N-nitrosomethylethylamine, 14C-labeled in either the methyl or ethyl group (survival time, 4 h). DNA was analyzed by Sephasorb-HP chromatography following acid hydrolysis in 0.1 M HCl. Concentrations of 7-methylguanine in hepatic DNA were 170-200 times higher than those of 7-ethylguanine. This is approximately 2.6 times the 7-methylguanine:7-ethylguanine ratio of 68, observed when DNA is reacted in vitro with equimolar amounts of the direct alkylating agents N-nitrosomethylurea and N-nitrosoethylurea, suggesting that hydroxylation at the alpha-position of the ethyl group of N-nitrosomethylethylamine proceeds at about 2.6 times the rate as at the methyl group. Concentrations of 7-methylguanine in liver were approximately 15 times higher than in kidney, 100 times higher than in esophagus, and 200 times higher than in lung. Addition of ethanol to the drinking water (5%) caused a slight interorgan shift in metabolism with a decrease in the 7-methylguanine ratio for liver:esophagus by 50% and an increase in the 7-methylguanine ratio for liver:kidney by 40%.

Alkylation↗
PubMed1985

Comparative study on the carcinogenicity of N-nitroso-2,6-dimethylmorpholine in the European hamster.

The effect of N-nitroso-2,6-dimethylmorpholine (NDMM), a pancreatic carcinogen for the Syrian golden hamster, was examined in the European hamster (EH) for comparative reasons. The compound was administered by subcutaneous (SC) injection or intragastric gavage (IG) at a dose level corresponding to 0.1 of LD50. In terms of carcinogenicity the main target was the respiratory epithelium (nasal cavity, lung, trachea, larynx); other benign and malignant tumors originated in the liver (bile duct epithelium and endothelium) and renal pelvis (transitional epithelium). The occurrence of neoplasms seen at other sites was difficult to attribute to treatment. Reduced metabolism as found during hibernation did not change the organ distribution of neoplastic growths. Differences in the carcinogenic potency (tumor incidence and latency, affected organs and cell types) did not depend significantly on the route of administration. The data were compared to those obtained using other nitroso compounds in this species.

Animals↗
PubMed1985

Carcinogenesis by oxygenated nitrosomethylpropylamines in Syrian hamsters.

Three oxygenated propylnitrosomethylamines were administered to female Syrian hamsters at doses similar to those which had induced high incidences of esophageal neoplasms in rats. Nitrosomethyl-2-oxopropylamine (NMOP) given at the rate of 2 mg/animal/week, whether as one application of 2 mg or two applications of 1 mg, led to early death of the animals, mostly with liver neoplasms; administration of 1 mg/animal/week led to longer survival, but most animals died with both liver neoplasms and neoplasms of the nasal mucosa. Only one hamster treated with NMOP had a neoplasm of the pancreatic duct. Of the 14 hamsters treated with the higher dose of nitrosomethyl-2-hydroxypropylamine (NMHP) and surviving beyond 6 weeks, most had liver neoplasms and nine had neoplasms of the pancreatic ducts. At the lower dose of NMHP, most hamsters developed neoplasms of the nasal mucosa, as did those receiving the same dose of NMOP, and seven animals had hemangioendothelial tumors of the liver, but only one animal had a carcinoma of the pancreatic duct. Nitrosomethyldihydroxypropylamine (NMDHP) was a much weaker carcinogen than the other two compounds and induced mainly neoplasms of the nasal mucosa, with little shortening of life.

Animals↗
PubMed1985

Lack of genetic and in vitro metabolic activity of potently carcinogenic azoxyalkanes.

4 carcinogenic azoxyalkanes (azoxymethane, azoxymethane and the 2 mixed methyl-ethyl compounds) were examined for activity in the Salmonella histidine reversion assay and in a lambda-lacZ prophage induction assay. Because azoxyalkanes are isomeric with nitrosodialkylamines, and might be expected to generate the same active intermediates, their biological activity was investigated under conditions which would allow direct comparison with these well-studied carcinogens. However, none of the azoxyalkanes, which are liver carcinogens, showed significant activity in either microbial assay in the presence of liver S9. In addition, metabolism studies with liver microsomes or hepatocytes indicated that the compounds were metabolized only to a small extent, if at all, under the conditions examined. This inactivity of the azoxyalkanes contrasts with the considerable activity in these assays - and the substantial metabolism - of the isomeric nitrosodialkylamines, also liver carcinogens. These results suggest that the carcinogenic action of azoxyalkanes proceeds through alternative metabolic pathways that are not adequately modeled by the assays and in vitro conditions used here.

Animals↗
PubMed1985

The metabolism and cellular interactions of some aliphatic nitrogenous carcinogens.

The alkylation of nucleic acids of the liver of rats and Syrian hamsters was measured in relation to carcinogenesis by a number of nitrosamines and azoxyalkanes, most of which induce tumors of the liver in both species following chronic treatment. Two compounds, nitroso-2,6-dimethylmorpholine and nitrosobis(2-hydroxypropyl)amine were not liver carcinogens in rats, but did induce liver tumors in hamsters; there was much less alkylation by these compounds in the rat than in the hamster. In both rats and hamsters, azoxymethane produced a greater extent of alkylation, both at N-7 and O-6 guanine, than did nitrosodimethylamine, although the former is no more potent than the latter as a carcinogen in either species. Both methyl groups of azoxymethane gave rise to N-7 methylation. Nitrosobis(2-oxopropyl)amine (BOP) and nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP) produced considerable methylation of liver nucleic acids in both species, comparable with that by nitrosodimethylamine, and they induce liver tumors in both rats and hamsters. However, in male rats the extent of alkylation by BOP was much smaller than in females and no O-6-methylation was detected in the former; this correlates with the failure of BOP to induce liver tumors in male rats by gavage, whereas liver tumors are induced in females.

Alkylation↗
PubMed1985

Induction of liver tumors in rats by nitrosodiethanolamine at low doses.

Nitrosodiethanolamine was given to male and female F344 rats in drinking water at three concentrations, 160, 64 and 28 mg/l. The highest dose was given for 50 weeks, the middle dose for 50 weeks and for 100 weeks, and the lowest dose for 100 weeks, the last to a group of 39 rats of each sex. The principal neoplasms that could be attributed to the treatment were hepatocellular carcinomas and neoplastic nodules in the liver. All of the female rats and 70% of male rats drinking 160 mg/l had hepatocellular neoplasms. At 64 mg/l the incidence of hepatocellular neoplasms was higher after 100 weeks administration than after 50 weeks, and was significantly higher than in controls after 100 weeks in both sexes. At 28 mg/ml there was a greater incidence of hepatocellular neoplasms than among controls only in the female rats. Nitrosodiethanolamine appears to be carcinogenic to F344 rats at quite low concentrations.

Animals↗
PubMed1985

Similar carcinogenic effects in rats of 1-ethyl-1-nitroso-3-hydroxyethylurea and 1-hydroxyethyl-1-nitroso-3-ethylurea.

The two isomeric N-nitroso derivatives of the dialkylurea, 1-ethyl-3-(2-hydroxyethyl)urea, were given by gavage to 20 male F344 rats for 30 weeks at equimolar doses. The tumorigenic responses were compared with those to a similar dose of nitrosoethylurea or nitroso-2-hydroxyethylurea. Each of the nitrosomonoalkylureas caused death from tumors more rapidly than the analogous nitrosodialkylurea. Each of the nitrosodialkylureas induced a broader spectrum of tumors in the rats than did either nitrosoethylurea or nitroso-2-hydroxyethylurea, including neoplasms of the thyroid, lung, skin, colon, mesotheliomas and neoplasms of the brain and liver in high incidence, the last two of which were not seen in animals given the nitrosomonoalkylureas. On the other hand, there were fewer tumors of the forestomach in rats given the nitrosodialkylureas than with the nitrosomonoalkylureas. The major difference between 1-nitroso-1-ethyl-3-hydroxyethylurea and 1-nitroso-1-hydroxyethyl-3-ethylurea was that the former induced only neoplastic nodules in the liver of 30% of the rats, while the latter induced hepatocellular carcinomas in 55% of the rats; approximately half of the rats given either compound had brain neoplasms, which included astrocytomas, gliomas and oligodendrogliomas.

Animals↗
PubMed1985

Comparative carcinogenesis by hydroxylated nitrosopropylamines in Syrian hamsters.

The relationship between the chemical structure of nitrosamines and their carcinogenic activity has been examined in Syrian golden hamsters in parallel with similar studies in rats to aid in explaining the sharp interspecies differences in response to these compounds. The relationship between the beta-oxidized N-propyl-nitrosamine structure and the induction of tumors of the pancreatic duct in Syrian golden hamsters was investigated by administration of a number of asymmetric acyclic nitrosamines containing that structure to female hamsters for 29-50 weeks. N-Nitroso-2-oxopropyl-2-hydroxyethylamine (OPE), N-nitroso-2-hydroxypropyl-2-hydroxyethylamine (NIEA), and N-nitroso-2,3-dihydroxypropyl-2-oxopropylamine (DHPOP) induced pancreatic tumors. OPE also induced a high incidence of liver neoplasms, and a number of animals given NIEA and N-nitrosoallyl-2-oxopropylamine (NAOP) also had liver neoplasms. N-Nitroso-2,3-dihydroxypropyl-2-hydroxyethylamine was very weakly carcinogenic. N-Nitroso-2,3-dihydroxypropyl-2-hydroxypropylamine and DHPOP induced a high incidence of neoplasms of the forestomach (mainly papillomas). N-Nitrosoallyl-2,3-dihydroxypropylamine, N-nitrosoallyl-2-hydroxypropylamine, and NAOP induced primarily neoplasms of the nasal mucosa but no neoplasms of the pancreatic ducts in hamsters.

Animals↗
PubMed1985

Organ-specific carcinogenesis in rats by methyl- and ethylazoxyalkanes.

Azoxyalkanes are isomeric with nitrosodialkylamines and could be similar in their biochemical and biological actions. To compare the structure-activity relations in the two series, the tumorigenic activities of four azoxyalkanes, azoxymethane, azoxyethane, Z-ethyl-O,N,N-azoxymethane, and Z-methyl-O,N,N-azoxyethane, were compared in male F344 rats by p.o. administration of 0.54 mM and 0.135 mM solutions in drinking water. In most cases, treatment lasted 30 weeks, but at the higher dose of the two ethylazoxy compounds, 24 weeks of treatment were sufficient. Most of the animals died with tumors that could be attributed to the treatments. The two ethylazoxy compounds caused much earlier death from tumors than the corresponding methylazoxy compounds. All four compounds induced a high incidence of liver neoplasms, which were mainly hepatocellular; the two ethylazoxy compounds also induced a large number of hemangiosarcomas in the liver. At both dose levels, azoxyethane induced tumors of the esophagus and nasal cavity, tumors that were not seen in any other group. Other tumors appearing in significant incidence were in the colon and ileum, induced by azoxymethane and Z-ethyl-O,N,N-azoxymethane, and kidney tumors induced by azoxymethane and Z-methyl-O,N,N-azoxyethane. In F344 rats, azoxyethane was similar in carcinogenic activity to its isomer nitrosodiethylamine, whereas azoxymethane was much less potent than nitrosodimethylamine and induced quite different tumors. These results suggest that the biochemical activation of azoxylkanes is different from the analogous nitrosodialkylamines.

Animals↗
PubMed1985

Carcinogenic effect of nitrosoalkylureas and nitrosoalkylcarbamates in Syrian hamsters.

Three nitrosoalkylureas, two nitrosotrialkylureas, and three nitrosoalkylcarbamates were given to Syrian golden hamsters by gavage at approximately equimolar doses. Measured by the time to death with tumors as an index, nitrosoethylurea was the most potent carcinogen, followed by nitroso-2-hydroxyethylurea, which was less effective in males than in females. The least effective compounds, by this measure, were nitrosooxazolidone and nitroso-5-methyloxazolidone. The remaining compounds, nitroso-N-ethylurethan, nitroso-2-hydroxypropylurea, nitrosomethyldiethylurea, and nitrosotriethylurea appeared to be of similar potency. All of the compounds induced papillomas or carcinomas of the nonglandular stomach in high incidence, except in the groups given nitrosohydroxyethylurea or nitrosooxazolidone; exceptionally, only 35% of the latter group had tumors, compared with 70% or more in the other groups. All of the nitrosoalkylureas induced a high incidence of hemangiosarcomas of the spleen, but the nitrosoalkylcarbamates did not. The quite uniform response of the hamster to these compounds contrasts with the great variety of organs and cell types in which they induce tumors in the rat.

Animals↗
PubMed1984

Atrial thrombosis involving the heart of F-344 rats ingesting quinacrine hydrochloride.

Quinacrine hydrochloride is toxic for the heart of F-344 rats. Rats treated with 500 ppm quinacrine hydrochloride in the diet all developed a high incidence of left atrial thrombosis. The lesion was associated with cardiac hypertrophy and dilatation and focal myocardial degeneration. Rats died from cardiac hypertrophy with severe acute and chronic congestion of the lungs, liver, and other organs. Seventy percent of rats given 250 ppm quinacrine hydrochloride and 1,000 ppm sodium nitrite simultaneously in the diet had thrombosis of the atria of the heart, while untreated control rats in this laboratory did not have atrial thrombosis. Sodium nitrite in combination with quinacrine hydrochloride appeared to have no additional effect.

Animals↗
PubMed1984

Species differences in nitrosamine carcinogenesis.

The carcinogenic action of approximately 50 N-nitroso compounds, nitrosamines, and nitrosoalkylamides has been compared in rats and in Syrian golden hamsters. The compounds were administered PO, as far as possible at comparable dose rates. The relative potencies of the treatments were assessed mainly by the time to death of the animals with tumors. The esophagus and other parts of the upper gastrointestinal tract were the most common sites for tumor induction in rats, but the esophagus was hardly ever affected in hamsters, although several compounds induced tumors of the forestomach in both rats and hamsters. No conclusion could be drawn about the relative susceptibility of the rat and hamster to these N-nitroso compounds, which varied with different compounds. Few generalizations can be made about these results, although it appeared that the 2-hydroxypropyl group was usually necessary for the induction of pancreas tumors in hamsters.

Alkylation↗
PubMed1984

Carcinogenesis in F-344 rats by nitrosobis(2-oxopropyl)amine and related compounds administered in drinking water.

Three asymmetric nitrosamines related to nitrosobis-(2-oxopropyl)-amine (BOP) were given to female F344 rats in drinking water to assess the significance of other alkyl groups on the carcinogenic expression by the 2-oxopropyl group. Nitroso-oxopropylethanolamine (OPE) was weakly carcinogenic, leading to little life-shortening and to induction of tumors (most of them liver neoplasms) in less than half of the treated animals. BOP under these conditions induced a high incidence of hepatocellular carcinomas and hemangiosarcomas of the liver together with lung adenomas in most animals. At the same dose rate nitrosohydroxypropyl-oxopropylamine (HPOP) induced hepatocellular carcinomas, lung carcinomas, and carcinomas of the esophagus with a high incidence; life-shortening was greater with HPOP than with BOP. At a higher dose rate HPOP again induced a high incidence of esophageal carcinomas, and of liver neoplasms, but more animals had hemangiosarcomas than hepatocellular carcinomas. Nitrosodihydroxypropyl-oxopropylamine (DHPOP) increased the mortality rate due to tumors by much more than the other three compounds, but induced mainly tumors of the upper gastrointestinal tract and no neoplasms in the liver. These results do not support the concept that BOP acts through reduction to HPOP, but suggest rather that the nature of the substituents other than 2-oxopropyl in the analogs of BOP has a profound influence on the potency and organ-specificity of the carcinogen. It is probable that pharmacokinetics and the specificity of activation of the particular molecular structures play an important role.

Animals↗
PubMed1984

Comparative metabolism of the cis and trans isomers of N-nitroso-2,6-dimethylmorpholine in rats, hamsters and guinea pigs.

The in vivo metabolism of the cis and trans isomers of N-[3,5-3H]nitroso-2,6-dimethylmorpholine (NDMM) was studied in female Fischer rats, Syrian golden hamsters and guinea pigs by analysis of urinary metabolites using high pressure liquid chromatography (HPLC). Animals were treated by gavage with 12 mg/kg body wt. of NDMM, composed of both isomers and 12 microCi/kg body wt. of either of the separated radioactive isomers (cis or trans). Control animals received 12 mg, 12 microCi/kg body wt. NDMM with both isomers labeled in their natural proportion. There was a substantial increase in the excretion of a particular metabolite, 2-(2-hydroxyl-methyl)ethoxy propanoic acid, in the urine of rats, hamsters and guinea pigs 24 h after received the trans isomer (24, 22 and 13% of the total dose excreted, respectively). A minor metabolite was determined to be 2,6-dimethylmorpholine-3-one, another product of alpha-oxidation. The metabolite 1-amino-2-hydroxypropanol was identified, indicating that NDMM was metabolized by both alpha- and beta-oxidation. In all three species, animals administered the cis isomer excreted larger amounts of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) and N-nitroso-bis(2-hydroxypropyl)amine (BHP) products of beta oxidation, than those treated with the trans isomer. Hamsters and guinea pigs treated with the more carcinogenic cis isomer in these species, also excreted twice as much of two other metabolites than was found in the urine of animals given the trans isomer. The trans isomer of NDMM appeared to be preferentially metabolized by alpha-oxidation and from earlier studies this metabolic pathway seemed to be important in carcinogenesis by NDMM in the rat. The cis isomer might be in a conformation more favorable for beta-oxidation and this pathway may be of primary importance in carcinogenesis by NDMM in hamsters and guinea pigs.

Animals↗