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Biomedical subjects

J Althoff

Publications and source records attributed to J Althoff.

At least 91 records · Page 5Linked to original sources
PubMed1978

Carcinogenicity and metabolic profiles of 6-substituted benzo[a]pyrene derivatives on mouse skin.

The ability was tested of appropriate substituents of benzo[a]pyrene (BP) at C-6 to decrease or suppress the carcinogenic activity for these BP derivatives relative to the parent compound. 8-week-old female Swiss mice in 9 groups of 30 were treated on the back with 0.2 mumol of compound in acetone 4 times weekly for 20 weeks. The following compounds were administered: BP, 6-methylbenzo[a]pyrene (BP-6-CH3), 6-hydroxymethylbenzo[a]pyrene (BP-6-CH2OH), benzo[a]pyrene-6-carboxaldehyde (BP-6-CHO), benzo[a]pyrene-6-carboxylic acid, 6-methoxybenzo[a]pyrene, 6-acetoxybenzo[a]pyrene, 6-bromobenzo[a]pyrene, and 6-iodobenzo[a]pyrene. Two additional groups received BP or BP-6-CH3 twice weekly for 20 weeks at a total dose 25% of that above. In addition, the metabolism of selected 6-substituted BP derivatives was studied, using mouse skin homogenates in vitro and mouse skin in vivo. Only four compounds were carcinogenic; the order of potency was BP greater than BP-6-CH3 greater than BP-6-CH2OH and BP-6-CHO. The difference in carcinogenicity between BP-6-CH2OH and BP-6-CHO could not be assessed by this experiment. In a further tumorigenesis experiment the carcinogenicity of BP-6-CH2OH was compared to that of BP-6 CHO, BP-6-CH3 and 6-hydroxymethylbenzo[a]pyrere sulfate ester (BP-6-CH2OSO3Na) on mouse skin. 9-week-old female Swiss mice in groups of 28 were treated at three dose levels with 0.8, 0.2 and 0.05 mumol of compounds in dioxane--dimethyl sulfoxide (75 : 25) twice weekly for 40 weeks. After 40 experimental weeks BP-6-CH2OSO3Na proved to be a more potent carcinogen than BP-6-CH2OH, which, in turn was more active than BP-6-CHO. The greater carcinogenicity of BP-6-CH3 relative to BP-6-CH2OH and BP-6-CHO is confirmed, suggesting that BP-6-CH2OH is not a proximate carcinogenic metabolite for BP-6-CH3. Since BP-6-CHO is a weaker carcinogen than BP-6-CH2OH and is efficiently reduced metabolically to BP-6-CH2OH, the latter compound may be a common proximal carcinogenic metabolite. The stronger potency of BP-6-CH2OSO3Na, compared to its alcohol, suggests that an ester of BP-6-CH2OH might be the ultimate alkylating compound reacting with cellular nucleophiles.

Animals↗
PubMed1978

Carcinogenicity and metabolic profiles of 3-methylcholanthrene oxygenated derivatives at the 1 and 2 positions.

Trapping of 3-methylcholanthrene (MC) radical cation by nucleophilic compounds occurs specifically at the 1-carbon atom. With the purpose of providing more evidence for the hypothesis that the critical mechanism of activation of MC is one-electron oxidation, the carcinogenicity of MC was compared to that of 1-hydroxy-3-methylcholanthrene (MC-1-OH), 3-methylcholanthrene-1-one (MC-1-one), 2-hydroxy-3-methylcholanthrene (MC-2-OH), 3-methylcholanthrene-2-one (MC-2-one) and 3-methylcholanthrylene (MCL) by repeated application on mouse skin. Seven-week-old female Swiss mice in 6 groups of 30 were treated on the back with 0.2 mumol of compound in acetone twice weekly for 20 weeks. In addition, the metabolism of MC and its derivatives was studied using mouse skin homogenates. The compounds tested were classified according to carcinogenicity in 4 groups: MC and MC-2-OH, the strongest carcinogens; MC-2-one and MCL, weaker than MC and MC-2-OH; MC-1-OH, the weakest carcinogen; and MC-1-one, non-carcinogenic. These results support the hypothesis that one-electron oxidation for MC, MC-2-OH and MC-1-one might be the critical mechanism of carcinogenic activation, with C-1 the binding site to cellular nucleophiles. The carcinogenic effect of MC-1-OH is speculated to be the formation of an ester bearing a good leaving group, which might be the ultimate alkylating compound in the in vivo reaction. The lack of carcinogenic activity for MC-1-one may be attributed to absence of nucleophilic trapping at C-1 via the radical cation pathway as well as the inability of mouse skin to reduce MC-1-one to the carcinogenic MC-1-OH.

Animals↗
PubMed1978

Carcinogenic effect of subcutaneously administered N-nitroso-2,6-dimethylmorpholine in Syrian golden hamsters.

N-Nitroso-2,6-dimethylmorpholine (DMNM) was examined in Syrian golden hamsters in a comparative study of N-N-dipropylnitrosamine (DPN) metabolites. DMNM was administered sc, and the results were compared with those of a previous study in which the compound was given intragastrically. DMNM was more toxic when administered sc, and the respiratory tract was the main target organ (with a 100% tumor incidence). With an sc administration, neoplasms occurred earlier in the hamsters than with an intragastric administration, and fewer tumors of the pancreas and biliary tract were found. However, neoplasms of the upper digestive tract and vagina were seen only with sc treatment. These studies indicated the importance of the treatment route but did not substantiate the role of common metabolites, such as DMNM, formed by beta-oxidation from DPN, with regard to induction of a given tumor type.

Animals↗
PubMed1977

The effect of 1-methoxypropylpropylnitrosamine in Syrian golden hamsters.

The carcinogenicity of the alpha-dipropylnitrosamine (DPN) methyl-ether, 1-methoxypropylpropylnitrosamine (1-MPPN), was investigated in Syrian hamsters for comparison with the effect of the alpha-DPN acetylester, 1-acetoxypropylpropylnitrosamine (1-APPN). It seemed possible that 1-MPPN, 1-APPN and DPN could form a common intermediate. However, contrary to the effect of 1-APPN, no tumors were found at the injection site after subcutaneous 1-MPPN treatment. The main target organ for 1-MPPN was the respiratory tract (as with DPN) and the lungs were greatly affected. In addition, pharyngeal and forestomach tumors occurred, and these were not observed after DPN administration. The results of 1-MPPN treatment, relative to DPN and 1-APPN, are discussed.

Animals↗
PubMed1977

Carcinogenicity of 1-oxopropylpropylnitrosamine (N-nitroso-N-propyl-proprionamide) in Syrian hamsters.

The effect of 1-oxopropylpropylnitrosamine (1-OPPN) was examined in Syrian hamsters. The subcutaneous (s.c.) LD50 was 308 mg/kg b.w. Animals treated s.c. once with a high dose of 1-OPPN had subcutaneous sarcomas and vaginal papillomas. Weekly s.c. injections for life led to high incidences of sarcomas at the injection site. In addition, 1-OPPN had a systemic effect. Neoplasms developed in the nasal cavity, larynx, trachea, lungs forestomach, and vagina. The results are discussed in connection with those found with other DPN derivatives substituted in the alpha-position.

Animals↗
PubMed1977

Urinary bladder neoplasms in Syrian hamsters after administration of N-nitroso-N-methyl-N-dodecylamine.

The biological effect of N-nitroso-N-methyl-N-dodecylamine (NMDA) was examined in Syrian hamsters as part of a comparative study. Data obtained show that after intragastric administration of NMDA, the urinary bladder was the main target organ for the carcinogenic effect. Transitional cell neoplasms developed and a positive dose response relationship was observed. Lung tumors occurred only in female hamsters, whereas males more frequently showed neoplasms of the nasal cavity and digestive tract.

Amines↗
PubMed1977

Transplacental effect of nitrosamines in Syrian hamsters. IV. Metabolites of dipropyl- and dibutylnitrosamine.

The present investigations showed that assumed and established metabolites of dipropylnitrosamine and dibutylnitrosamine reach the Syrian hamster fetus after subcutaneous (s.c.) treatment of their mothers (at day 14 of gestation). The compounds [2-hydroxypropylpropylnitrosamine, HPPN; 2-oxopropylpropylnitrosamine, OPPN; methylpropylnitrosamine, MPN; N-nitrosobis(2-hydroxypropyl)amine, BHP; and 4-hydroxybutylbutylnitrosamine, HBBN] were still present in the examined tissue (maternal blood, placenta, fetus, amniotic fluid) 4--6 h after s.c. injection. The overall incidence of transplacentally induced tumors was lower in the F1- than in the P-generation and comparatively longer latencies were also observed in the F1- generation. However, in some groups low incidences were found of tumors which did not occur in the mothers (i.e., nasal cavities: BHP, HBBN; trachea: HBBN; lungs: HPPN, BHP, HBBN; liver: OPN, MPN, BHP, HBBN). Compared to exposure at early gestation, the transplacental carcinogenic effect increased at day 14 of gestation. Neoplasms originating in other organs were not associated with a transplacental effect of the examined nitrosamines.

Amniotic Fluid↗
PubMed1977

Local and systemic effects of 1-acetoxypropylpropylnitrosamine in Syrian golden hamsters.

1-Acetoxypropylpropylnitrosamine (1-APPN) was synthesized and its biological effect examined in Syrian hamsters after subcutaneous (s.c.) administration. 1-APPN induced mesenchymal and epithelial neoplasms at the injection sites, as well as epithelial tumors in remote organs. Local neoplasms were a.c. sarcomas, mammary adenocarcinomas and Schwannomas, whereas tumors of the respiratory tract (papillary polyps, papillomas, adenomas, epidermoid carcinomas, and adenocarcinomas) were attributed to a systemic effect as were pancreas duct tumors. Neoplasms which originated in the upper digestive and genital tracts of females (papillomas, epidermoid carcinomas) may be related to a systemic and local effect of 1-APPN.

Animals↗
PubMed1977

Comparison of the effect of beta-oxidized dipropylnitrosamine metabolites administered at equimolar doses to Syrian hamsters.

After subcutaneous administration of dipropylnitrosamine (DPN) to Syrian hamsters, gas-liquid chromatographic analysis of the 16-h urine revealed the DPN metabolites, 2-hydroxypropyl-, 2-oxopropyl-, and methylpropylnitrosamines. In a related series of experiments, hamsters received equimolar doses of the above compounds and of N-nitrosobis(2-hydroxypropyl)-amine (BHP) and 2,2'-dimethyldipropylnitrosamine (DMDPN). The metabolites as well as BHP and DMDPN had a weaker effect than did DPN on the rate and/or latency of respiratory tumors. In the respiratory tract, the segmental tumor distribution and histological types varied according to the compounds. The metabolites of DPN induced additional tumors in the digestive tract. These experiments do not support the concept that the beta-oxidized metabolites of DPN are the proximate carcinogens of the parent compound.

Animals↗
PubMed1977

Transplacental effects of nitrosamines in Syrian hamsters. II. Nitrosopiperidine.

Nitrosopiperidine (NP) was found in Syrian hamsters quantitatively in the maternal blood for more than 8 h after subcutaneous injection, whereas it disappeared from placenta, fetus and amniotic fluid within the same time period. For N6MI, only traces were seen after 2 h in the same tissues. The long-term transplacental effect of a single dose of NP was weak, as demonstrated by a low respiratory tract tumor incidence (P-generation: 54%, F1- generation: 4%). Some tumors occurring in the digestive tract of exposed young were not found in their mothers and not commonly observed in controls. These tumors were considered a borderline transplacental effect. Tumors of other sites (i.e., the urogenital and genital tracts, reticuloendothelial system, endocrine organs and other tissues) corresponded in incidences to the overall fluctuations observed in this hamster colony.

Animals↗
PubMed1977

Transplacental effects of nitrosamines in Syrian hamsters. III. Dimethyl- and dipropylnitrosamine.

The aliphatic nitrosamines dimethylnitrosamine (DMN), diethylnitrosamine (DEN), dipropylnitrosamine (DPN), and dibutylnitrosamine (DBN) reached fetal tissue in quantitatively measurable amounts after subcutaneous administration to pregnant Syrian hamsters. The compounds were present for at least 2 h in maternal blood, placenta, fetus, and amniotic fluid; DBN was still measurable after 6 h. Only a weak or borderline transplacental effect was seen when incidences and latencies of neoplasms in the respiratory and digestive tracts of the F1-generation were compared with those of the P-generation after exposure to a single dose of DMN or DPN. However, some tumor types occurred at relatively high rates in the young, but were seen only occcasionally in their mothers or in this hamster colony in general.

Amniotic Fluid↗
PubMed1977

The effect of N-nitrosobis(2-oxopropyl)amine after oral administration to hamsters.

Oral administration of N-nitrosobis(2-oxopropyl)amine (BOP) in drinking water to Syrian golden hamsters for 90 days resulted in a high incidence of intra- and extrahepatic bile duct neoplasms. Only a few pancreatic neoplasms and no lung and kidney tumors developed, in contrast to results obtained after subcutaneous BOP administration.

Adenoma, Bile Duct↗
PubMed1977

Improvement of pancreatic cancer model by modified treatment with N-nitroso-bis (2-oxopropyl) amine.

Comparative studies were conducted in 2 groups of Syrian golden hamsters treated with N-nitroso-bis (2-oxopropyl)amine (BOP) weekly for life (group A) or weekly for 6 weeks (group B), and sacrificed at 2-week intervals. Pancreatic neoplasms developed as early as 8 weeks (group B) and 10 weeks (group A); however, in group B there were fewer, smaller lesions, well-differentiated morphologically. Liver neoplasms occurred only in group A, while gallbladder and kidney tumors were seen in both groups. A lower incidence of pulmonary adenomas was found in group B than in group A, which also had pulmonary carcinomas. The results indicate a further advance in the development of a pancreatic cancer model.

Adenocarcinoma↗
PubMed1977

Induction of epithelial neoplasms by local application of N-nitrosobis(2-hydroxypropyl)amine and N-nitrosobis(2-acetoxypropyl)amine.

The local carcinogenic effect of N-nitrosobis(2-hydroxypropyl)amine (BHP) and N-nitrosobis(2-acetoxypropyl)amine (BAP) in Syrian golden hamsters was elucidated by weekly application to the cheek pouch, lip and vaginal epithelium. The tumor type and incidence in BHP- and BAP-treated hamsters, respectively, was as follows: trichoepitheliomas of the lip, 80 and 90%; cheek pouch papillomas, 10 and 0%, and vaginal papillomas, 80 and 70%. Other lesions were recorded in the perineum, rectum and external urethral ostium and could have been due to a local effect of these nitrosamines. In addition, internal organ tumors were observed with each compound and were possibly caused by absorption of the carcinogens.

Animals↗
PubMed1977

Vinylethylnitrosamine: a potent respiratory carcinogen in Syrian hamsters.

Vinylethylnitrosamine (VEN), an alpha-beta unsaturated analogue of diethylnitrosamine (DEN), which may be formed by the enzymic conversion necessary for carcinogenesis, was synthesized and its biologic effect was examined by sc administration to Syrian hamsters. Distribution studies showed that the maximum amount of unaltered compound was found in various tissues 45 minutes after injection. The chemical was only partially excreted unchanged after 5 hours. Weekly treatment for life resulted in high incidence of malignant respiratory tract neoplasms with short latencies and in tumors of the upper digestive tract and pancreas. The effects of VEN were compared to those of the assumed parent compound, DEN.

Animals↗