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Biomedical subjects

D Hoffmann

Publications and source records attributed to D Hoffmann.

At least 325 records · Page 18Linked to original sources
PubMed1982

Influence of bay-region methyl group on formation of 5-methylchrysene dihydrodiol epoxide:DNA adducts in mouse skin.

The binding of tritium-labeled 5-methylchrysene to DNA of CD-1 mouse skin 24 hr after treatment has been studied. DNA was isolated from the treated skin areas of mice and hydrolyzed enzymatically to deoxyribonucleosides, and the hydrolysate was chromatographed on a Sephadex LH-20 column using a methanol:water gradient. The major adducts eluted between 70 and 100 ml (Peak 1), 470 and 590 ml (Peaks 2A to C), and 750 and 850 ml (peak 3). For identification of these products, markers were prepared from 5-methylchrysene bay-region dihydrodiol epoxides. [5-14C]1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene and [5-14C]7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-5-methylchrysene were synthesized by reacting the corresponding metabolically formed [5-14C]1,2-dihydro-1,2-dihydroxy-5-methylchrysene and [5-14C]7,8-dihydro-7,8-dihydroxy-5-methylchrysene with m-chloroperoxybenzoic acid. The structures of the dihydrodiol epoxides were established by their mass spectra and by hydrolysis to tetrols. Peak 2B was chromatographically indistinguishable, both on Sephadex LH-20 and reverse-phase high-pressure liquid chromatography, from the adduct formed when [5-14C]1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene was reacted with salmon sperm DNA in solution. Similarly, Peak 2A was chromatographically inseparable from the [5-14C]7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-5-methylchrysene:DNA adduct. Adduct 2B was formed to a greater extent than adduct 2A by the ratio of 2.7 to 1. These data indicate that 5-methylchrysene preferentially forms DNA adducts from the bay-region dihydrodiol epoxide adjacent to the methyl group.

Animals↗
PubMed1982

Tumor-initiating activity and metabolism of polymethylated phenanthrenes.

The tumor-initiating activity of several polymethylated phenanthrenes was determined in mouse skin. Among the compounds assayed were 1,4-, 1,9-, 2,7-, 3,6-, 4,5-, 4,9-, and 4,10-dimethylphenanthrene. Only the 1,4- and 4,10-dimethylphenanthrenes were active as tumor initiators. Initiating doses of 300 micrograms and 1.0 mg of 1,4-dimethylphenanthrene after promotion with tetradecanoylphorbol acetate induced 80 and 100% incidences of skin tumors in mice, respectively, 4,10-Dimethylphenanthrene assayed under identical conditions induced skin tumors in 35 and 55% of the mice. The in vitro metabolism of 1,4-, 3,6-, 4,9-, and 4,10-dimethylphenanthrene was studied by incubation of the compounds with the 9000 x g supernatant from the livers of Aroclor-pretreated rats. The major dihydrodiol metabolite of both 1,4- and 4,10-dimethylphenanthrene was the 7,8-dihydrodiol, the requisite precursor for the formation of bay-region dihydrodiol-epoxides. Dihydrodiols were not observed among the metabolites of 4,9-dimethylphenanthrene. In the case of 3,6-dimethyphenanthrene, the major diol metabolite formed in vitro was the 9,10-dihydrodiol. These results support previously proposed structural requirements which favor the carcinogenic activity of methylated polynuclear aromatic hydrocarbons. These studies indicate that tumorigenic activity of methylated phenanthrenes requires inhibition of dihydrodiol formation at the K-region (9,10-positions) in addition to a bay-region methyl group and a free peri position, both adjacent to an unsubstituted angular ring.

Animals↗
PubMed1982

N-nitrosodiethanolamine: analysis, formation in tobacco products and carcinogenicity in Syrian golden hamsters.

An analytical GC-TEA method has been developed for the quantitative determination of N-nitrosodiethanolamine (NDELA) in tobacco and tobacco smoke. US smoking and chewing tobaccos and experimental cigarette tobaccos contained between 80 and 420 micrograms/kg of NDELA. Two snuff samples contained 3200 and 6800 micrograms/kg of NDELA. NDELA in mainstream smoke of US cigarettes amounted to 10 - 68 ng per cigarette. Evidence was presented which incriminates diethanolamine as a major precursor for NDELA in tobacco and tobacco smoke. Diethanolamine is used as a solubilizing agent for maleic hydrazide, the major sucker-growth inhibitor for US tobacco crops. NDELA was bioassayed in Syrian golden hamsters by skin painting, swabbing of the oral cavity and by subcutaneous injection. Independently of the form of application, NDELA at the higher dose (500 mg/kg) induced carcinomas of the nasal cavity, papillomas of the trachea and tumours of the larynx in some animals. NDELA uptake through the oral cavity in hamsters is presumably greater than through the skin, judging by the higher tumour yield induced by painting of the oral cavity, compared to skin painting. Studies with 14C-labeled NDELA are currently underway to document this observation quantitiatively. The present analytical data for NDELA in tobacco and tobacco smoke, together with the carcinogenicity data reported here and elsewhere, strongly suggest a review of the use of maleic hydrazide-diethanolamine as sucker-growth inhibitor in the cultivation of tobacco and other crops.

Animals↗
PubMed1981

The influence of methyl substitution of the mutagenicity of nitronaphthalenes and nitrobiphenyls.

A series of nitrobiphenyls, nitronaphthalenes, and their methyl-substituted derivatives were assayed for mutagenicity toward S. typhimurium TA98 and TA100. In assays conducted in the absence of rat liver S9 fraction, substitution of a methyl group ortho to the nitro group decreased mutagenicity (3-methyl-4-nitrobiphenyl, 2-methyl-1-nitronaphthalene, and 3-methyl-2-nitronaphthalene). The mutagenicity of 4-nitrobiphenyl was also inhibited by methyl substitution at the 2'-position (2'-methyl-4-nitrobiphenyl), and at both the 3- and 2'-positions (3,2'-dimethyl-4-nitrobiphenyl). In assays conducted in the presence of rat liver S9 fraction, inhibition of mutagenicity by methyl substitution was demonstrated for 2-methyl-1-nitronaphthalene, 3-methyl-2-nitronaphthalene and 3,2'-dimethyl-4-nitrobiphenyl. Thus, methyl substitution of nitrobiphenyls and nitronaphthalenes generally decreased mutagenicity, when assays were conducted in the absence of rat liver S9 fraction. However, in the presence of rat liver S9 fraction, the inhibitory effect of methyl substitution on mutagenicity was less pronounced. These results contrast to the usual enhancing effect of ortho-methyl substitution of the corresponding aromatic amines and their N-oxidized derivatives (hydroxylamines and C-nitroso compounds).

Animals↗
PubMed1981

Mutagenicity of aminocarbazoles and nitrocarbazoles.

The mutagenic activity of all 4 isomeric aminocarbazoles and 4 nitrocarbazoles was evaluated in Salmonella typhimurium tester strains TA98. TA100 and TA1535. All compounds were assayed both in the presence and absence of liver homogenate from Aroclor-treated rats. Among the aminocarbazoles, 2-aminocarbazole was found to be most active in both tester strains, although somewhat less active than 2-aminofluorene. 3-Aminocarbazole was the only other isomer that was mutagenic towards TA98 at the dose levels employed (5--200 micrograms). 4-Aminocarbazole was moderately active in TA100, and 1-aminocarbazole was inactive in both TA98 and TA100. Similar differences in mutagenic potency and specificity towards the tester strains were observed for the related series of nitrocarbazoles.

Amines↗
PubMed1981

Mutagenicity of methylated fluorenes and benzofluorenes.

Methylated fluorenes were assayed for mutagenic activity towards Salmonella typhimurium TA98 and TA100. None of these methylfluorenes were mutagenic in the absence of metabolic activation. In the presence of 9000 X g supernatant from Aroclor-induced rats, 9-methylfluorene and 1,9-dimethylfluorene were active towards TA98 and TA100. The structural requirement for mutagenic activity within this series was the presence of a single methyl substituent at the 9-position. Enhanced mutagenic activity was also observed for benzofluorenes similarly methylated at their benzylic positions.

Animals↗
PubMed1981

Assessment of the carcinogenic N-nitrosodiethanolamine in tobacco products and tobacco smoke.

A simple, reproducible gas chromatography-thermal energy analyzer (g.c.-TEA) method has been developed for the analysis of N-nitrosodiethanolamine (NDELA) in tobacco and tobacco smoke. The extract of tobacco or the trapped particulates of tobacco smoke are chromatographed on silica gel. The NDELA containing fractions are concentrated, silylated and analyzed with a modified g.c.-TEA system. [14C]NDELA serves as internal standard for the quantitative analysis. Experimental cigarettes made from tobaccos which were treated with the sucker growth inhibitor maleic hydrazidediethanolamine (MH-DELA) contained 115--420 p.p.b. of NDELA and their smoke contained 20--290 ng/cigarette, whereas hand-suckered tobacco and its smoke were free of NDELA. The tobacco of US smoking products contained 115--420 p.p.b. of NDELA and the mainstream smoke from such products yielded 10--68 ng/cigar or cigarette. NDELA levels in chewing tobacco ranged from 220--280 p.p.b. and in two commercial snuff products were 3,200 and 6,800 p.p.b. Although the five analyzed MH-DELA preparations contained between 0.6--1.9 p.p.m. NDELA it is evident that the major portion of NDELA in tobacco is formed from the DELA residue during the tobacco processing. Based on bioassay data from various laboratories which have shown that NDELA is a relatively strong carcinogen and based on the results of this study the use of MH-DELA for the cultivation of tobacco is questioned.

Carcinogens↗
PubMed1981

Immunotherapy of bovine ocular squamous cell carcinomas with phenol-saline extracts of allogenic carcinomas.

Forty cattle with unilateral ocular squamous cell carcinomas and 2 with bilateral carcinomas were treated with a single intramuscular injection of a phenol-saline extract of allogeneic bovine ocular squamous cell carcinoma. Doses of extract varied from the equivalent of 100 mg of lyophilised powder to the equivalent of 1500 mg of lyophilised powder. Thirty-three of the 44 carcinomas (78%) responded to treatment, 15 regressing completely, 9 losing at least 50% of their bulk and 9 ceasing to increase in bulk. The response was significantly better (p less than 0.05) in cattle receiving 200 mg or more of lyophilised powder than in those receiving 100 mg of powder. Some 30 of 34 carcinomas (88%) responded to treatment when 200 mg or more of lyophilised powder was used. Five cattle with ocular carcinomas that had failed to respond to the initial treatment and 8 that had responded incompletely received second doses of phenol-saline extracts of allogeneic carcinomas. One carcinoma regressed completely and 2 regressed partially. Thirty cattle with untreated ocular squamous cell carcinomas were observed for periods of from one to 9 months. All the carcinomas grew progressively. Seventeen cattle with ocular squamous cell carcinomas were treated with phenol-saline extracts of bovine cutaneous papilloma, bovine foetal skin or normal bovine cornea and conjunctiva and observed for periods of from one to 14 months. A carcinoma in an animal treated with 500 mg of powder from an extract of cutaneous papilloma did not increase in size over the next 31 weeks. The other carcinomas grew progressively.

Animals↗
PubMed1981

A study of tobacco carcinogenesis. XX. Role of catechol as a major cocarcinogen in the weakly acidic fraction of smoke condensate.

The weakly acidic fraction of cigarette smoke condensate was fractionated by preparative high-pressure liquid chromatography into major subfractions I-IV. Major subfractions II and III were fractionated further into subfractions A-J. Subfractions A-J were tested for cocarcinogenicity on the skin of noninbred Ha:ICR Swiss albino mice by application with 0.003% benzo[a]pyrene. Subfractions A-C and F-J showed significant cocarcinogenic activity; subfractions A, F, and H were the most active. Catechol was a major component of subfraction A and was also detected in subfractions B-D and F. Major components of the other subfractions included hydroquinone (B), coniferyl alcohol (C and H), hydroxyphenyl alcohols (D), alkyl-2-hydroxy-2-cyclopenten-1-ones (C, D, and F), hydroxyacetophenones (F), phenolic cyano compounds (F), and fatty acids (F). The results demonstrate the importance of catechol as a cocarcinogen in the weakly acidic fraction of cigarette smoke condensate and indicate the presence of other cocarcinogens.

Animals↗
PubMed1981

Carcinogenic tobacco-specific N-nitrosamines in snuff and in the saliva of snuff dippers.

Human data indicate an increased risk for cancer of the oral cavity for snuff dippers. Popular snuff products from the United States, Germany, Sweden, and Denmark were analyzed for tobacco-specific N-nitrosamines (TSNA). These compounds are formed during tobacco processing from nicotine, nornicotine, and anatabine and represent the only known carcinogens in snuff. N'-Nitrosonornicotine, a moderately active carcinogen, ranged in dry snuff from 3.5 to 77 ppm; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a relatively strong carcinogen, ranged from 0.6 to 7.0 ppm; and N'-nitrosoanatabine, thus far not bioassayed, ranged from 0.8 to 44 ppm. The concentrations of TSNA in a given snuff product can vary widely, and aging in the open air can lead to an increase in TSNA. Analysis of the saliva of snuff dippers revealed that these nitrosamines are extracted from the tobacco plug during snuff dipping and that their concentrations in saliva can vary widely between users. Efforts should be made to reduce the TSNA in snuff by modifications of the production process and by wrapping individual snuff portions in airtight packets.

Adult↗
PubMed1981

Comparative carcinogenicity and metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosonornicotine in Syrian golden hamsters.

The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) were tested for carcinogenic activity in Syrian golden hamsters. In Assay A, 30 hamsters were each given 19 s.c. injections of 0.048 mmol of NNK or NNN. In Assay B, 20 hamsters each received 75 s.c. injections of 0.012 mmol of NNK or NNN. Among the NNK-treated hamsters in Assay A, three developed carcinomas of the nasal cavity, and 19 had adenomas and/or adenocarcinomas of the lung. In the NNN group, one hamster developed a lung adenoma, and five had tracheal papillomas. In Assay B, 11 of the NNK-treated hamsters developed carcinomas of the nasal cavity, 16 had lung adenomas and/or adenocarcinomas, and seven had tracheal papillomas; in the NNN group, we recorded only one hamster with a lung adenoma and one with a tracheal papilloma. These findings in the Syrian golden hamster confirm that NNK is a more powerful carcinogen than NNN, as was shown previously in assays with rats and mice. In metabolism studies, 96 to 98% of the radioactivity of the injected [1-14C]NNK was recovered in the urine, 4% was recovered in the feces, and less than 0.5% was recovered as exhaled 14CO2. The corresponding distribution for [2'-14C]NNN was 62 to 78% in urine, 10% in feces, and less than 0.5% in respiratory 14CO2. The levels of binding of [1-14C]NNK and [2'-14C]NNN to the trichloroacetic acid-insoluble fractions were highest in liver, lung, kidney, and adrenals. The urinary metabolites of NNK and NNN resulted from alpha-hydroxylation, from N-oxidation of NNN to N'-nitrosonornicotine-1-N-oxide, and from reduction of NNK to 4-(methylnitrosamino)-1-(3-pyridyl)butan-1-ol.

Animals↗
PubMed1981

Reduction of tumorigenicity and of dihydrodiol formation by fluorine substitution in the angular rings of dibenzo(a,i)pyrene.

The tumor-initiating activities on mouse skin and in vitro metabolism of dibenzo(a,i)pyrene, 2-fluorodibenzo(a,i)pyrene, 3-fluorodibenzo(a,i)pyrene, and 2, 10-difluorodibenzo(a,i)pyrene were compared. After an initiating dose of 500 micrograms, followed by promotion with tetradecanoylphorbol acetate, dibenzo(a,i)pyrene induced skin tumors in 85% of the mice and caused 5.8 skin tumors/mouse. The corresponding tumorigenic activities for the fluorinated compounds were: 2-fluorodibenzo(a,i)pyrene (85%; 1.7 tumors/mouse); 3-fluorodibenzo(a,i)pyrene (80%; 3.1 tumors/mouse); and 2,10-difluorodibenzo(a,i)pyrene (10%; 0.1 tumors/mouse). After an initiating dose of 100 micrograms, only dibenzo(a,i)pyrene showed significant tumor-initiating activity. 3,4-Dihydro-3,4-dihydroxydibenzo(a,i)pyrene was identified as a metabolite of dibenzo(a,i)pyrene formed by the 9000 X g supernatant from the livers of Aroclor 1254-pretreated rats. Another dihydrodiol was tentatively identified as 1,2-dihydro-1,2-dihydroxydibenzo(a,i)pyrene. The formation of these angular ring dihdrodiols was inhibited in the metabolism of 2-fluorodibenzo(a,i)pyrene and 3-fluorodibenzo(a,i)pyrene. Angular ring dihydrodiols were not detected in the metabolism of 2,10-difluorodibenzo(a,i)pyrene. These results suggest that an angular ring dihydrodiol, 3,4-dihydro-3,4-dihydroxydibenzo(a,i)pyrene, which can form a bay-region dihydrodiol epoxide, may be a proximate carcinogen of dibenzo(a,i)pyrene.

Animals↗
PubMed1981

Autografting and allografting of bovine ocular squamous cell carcinoma.

The autografting and allografting of bovine ocular squamous cell carcinoma was attempted. Autologous transplantation of primary ocular squamous cell carcinoma to subcutaneous sites initiated tumour growth at some sites in 11 of 17 animals when tumour pieces were used. The transplanted tumours showed progressive growth after a latent period of one to 10 weeks and attained a size of 1 cm between two and 16 weeks after implantation. Autologous tumour pieces also grew in the thoracic cavity of one animal but failed to grow in the peritoneal cavity of this animal and three other cattle. Tumour pieces obtained from subcutaneous autografts of two animals were reduced to single cell suspensions by trypsinisation at 37 degrees C and 4 degrees C. Each of these animals received five subcutaneous injections of 15 X 10(6) viable autologous cells per site for each preparation. No progressive growth was recorded at these sites. Autologous cultured tumour cells also failed to initiate progressive growth in two animals receiving 5 X 10(6) and 15 X 10(6) viable cells respectively. Pieces of subcutaneous autografts were reimplanted on five animals and progressive tumour growth was initiated on all five animals. In one animal the tumour pieces used for reimplantation had been stored in a liquid nitrogen refrigerator for seven days. Allografting was successful in only one of 10 attempts. The allograft grew until 10 weeks after implantation, then regressed spontaneously. No spontaneous regression was seen with autografts after progressive growth was recorded.

Animals↗
PubMed1981

Carcinogenicity in Syrian golden hamsters of N-nitrosamines formed during nitrosation of spermidine.

Several N-nitrosamines are formed during the nitrosation of the polyamines, spermidine and spermine. Since these polyamines may represent a source for the endogenous or exogenous formation of N-nitrosamines, their major nitrosation products were assayed for carcinogenicity in male Syrian golden hamsters. Administration of N-nitroso-3-butenyl(2-propenyl)amine SC once a week for life at a dose of 300 mg/kg induced neoplasms mostly in the upper respiratory tract (nasal cavity, larynx, trachea). Lung microlithiasis (alveolar and bronchial) also developed in all these animals. In contrast, N-nitroso-3-butenyl(3-hydroxypropyl)amine and N-nitroso-4-hydroxybutyl(2-propenyl)amine induced neoplasms, primarily in the digestive tract, including the nonglandular stomach, cecum, colon, and adrenal gland.

Animals↗