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Biomedical subjects

D Hoffmann

Publications and source records attributed to D Hoffmann.

At least 289 records · Page 16Linked to original sources
PubMed1984

A study of betel quid carcinogenesis. II. Formation of N-nitrosamines during betel quid chewing.

In model studies, nitrosation of the major areca alkaloid, arecoline, leads to the formation of N-nitrosoguvacoline, 3-(methylnitrosamino)propionitrile (MNPN), 3-(methylnitrosamino)propionaldehyde and two unknown N-nitrosamines. MNPN is a strong carcinogen in Fischer 344 rats. After subcutaneous injection of 1.1 mmol MNPN in 60 doses, all 15 male and 15 female rats developed tumours within 24 weeks; multiple tumours occurred in 26 of the rats. Eighty-seven percent of the animals had tumours of the oesophagus, 70% had nasal cavity tumours, 37% had tumours of the tongue, 7% tumours of the pharynx and 7% tumors of the forestomach. At the dose used, male and female rats showed no significant difference in tumour incidence or site of tumours. The formation of MNPN during betel quid chewing, although likely, has not yet been proven, while the areca-derived N-nitrosamine, N-nitrosoguvacoline (NG), has been found in the saliva of betel quid chewers at levels of 2.2-348 micrograms/L. N-Nitrosoguvacoline levels were higher in the saliva of chewers who used betel quid together with tobacco. The saliva of these chewers also contained tobacco-specific N-nitrosamines.

Animals↗
PubMed1984

Demographic aspects of the low-yield cigarette: considerations in the evaluation of health risk.

Control data from a large-scale case-control study of tobacco-related diseases were analyzed to characterize variables associated with cigarette preference (or type of cigarette smoked). Age, sex, race, education, and religion were found to have a strong influence on the choice of cigarette according to tar and nicotine yield. Data on the amount and duration of cigarette smoking also were evaluated by brand history to determine whether tar yield was associated with these variables. Women smoking cigarettes in the low-tar categories tended to smoke fewer cigarettes per day than women smoking cigarettes in the higher tar categories. A similar trend was not found for men. As might be expected, only 2% of the men and 3% of the women over the age of 40 smoked low-tar cigarettes (less than 10 mg tar) for 10 years or more.

Adult↗
PubMed1983

Analysis of network flow distribution: computational aid to minimize experimental expenditure.

Several problems in microvascular research, e.g., total blood flow and red cell flux distribution, can only be solved by evaluating the flow distribution to all branches of microvessel networks. We present a method to obtain values of volumetric blood flow and red cell flux in individual networks by taking measurements in an adequately chosen number of the vessels (50-33%) in the network. Actual measurements are not mandatory in all vessels because in a major part of them computational quantification of flows and fluxes is possible. The proposed method consists of a procedure to document in matrix form the connections of a network found in a preparation. By appropriate mathematical manipulations of the matrix, a preselection of measuring sites within the network can be achieved. From the flow values in these sites the remaining vessel flows can be calculated by utilizing the law of mass conservation in all branching points and confluxes. The worst case error of the procedure can be calculated from the errors of the single measurements. The method can also be applied, whenever, for experimental reasons (e.g., poor microscopic focus, flow too rapid or too slow), certain branches do not lend themselves for measurement. A BASIC program can be made available upon request, which carries out all calculations necessary for an appropriate selection in such a short time (about 1 min) so that it can easily be performed before the start of data acquisition.

Animals↗
PubMed1983

Mutagenicity of substituted phenanthrenes in Salmonella typhimurium.

An extensive series of alkylated phenanthrenes was assayed for mutagenic activity in Salmonella typhimurium TA98 and TA100. Among the alkylated phenanthrenes assayed, 1-methylphenanthrene, 9-methylphenanthrene, 1,4-dimethylphenanthrene and 4,10-dimethylphenanthrene were active as mutagens. These studies suggest that the structural requirements favoring mutagenic activity among alkylated phenanthrenes are inhibition of 9,10-dihydrodiol formation and the presence of an unsubstituted angular ring adjacent to a free peri position. The mutagenic activities of 9-fluoro-, 9-chloro-, and 9-bromo-phenanthrene were also evaluated. The positive mutagenic response of these halogenated phenanthrenes further supports the observation that inhibition of 9,10-dihydrodiol formation among substituted phenanthrenes favors mutagenic activity.

Mutagenicity Tests↗
PubMed1983

On the formation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone during smoking.

Tobacco-specific N-nitrosamines (TSNA) are the most abundant carcinogens identified in tobacco and its smoke. Reducing their levels in tobacco products and especially in cigarette smoke is, therefore, a primary goal towards minimizing the carcinogenic burden of the tobacco consumer. This study delineates the mechanisms of formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the most powerful of the carcinogenic TSNA during cigarette smoking. It demonstrates, by means of radiolabeled tracer compounds that 6.9-11.0% of the NNK formed in tobacco during the curing process transfers into the mainstream smoke. This constitutes 26-37% of the NNK present in the smoke. Addition of [methyl-14C]-nicotine to cigarettes, prior to smoking, led to the finding that 0.001% of nicotine in the cigarette column appears in the smoke as NNK. Thus, 63-74% of NNK in smoke is formed during smoking. NNK yield in the smoke was independent of nitrate content of the tobacco. These data serve to devise methods of reducing TSNA in smoke.

Carbon Radioisotopes↗
PubMed1983

Normal urinary flow for girls aged 3-14 years.

103 healthy girls aged 3-14 in whom urological illness or chronic urinary tract infection could be ruled out were examined uroflowmetrically with a "Mictiograph" operating on the rotation-dynamic principle. The 103 girls were subdivided into 2 groups: 3-7 years (N:53) and 8-14 years (N:50). For both age groups we could establish uroflowmetric results (volume, micturition time, average flow, maximum flow, time required for attaining maximum flow) and subject them to statistical scrutiny. For all 5 uroflow parameters we figured the mean, variance, and standard deviation for both age groups. In a variance analysis we were able to document significant group differences for volume, average flow and maximum flow. Basing on these results it was possible to represent the correlation of average and maximum flow with volume for both age groups using lines of regression. Moreover, in the group aged 8-14 there existed a linear relation of volume, average flow and maximum flow to age. Naturally, some girls will continue to require a combined urodynamic examination. But by means of the statistically validated uroflow norms presented here, better differentiation from pathological results can be attained, and uroflow measurements in girls can now be regarded as reliable indicators.

Adolescent↗
PubMed1983

Induction of respiratory tract tumors in Syrian golden hamsters by a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the effect of smoke inhalation.

Four groups of 10 male and 10 female Syrian golden hamsters were given single s.c. injections of either 0.3 ml of trioctanoin or of 0.3 ml of trioctanoin containing either 1.0 mg, 3.3 mg, or 10.0 mg of the tobacco specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These hamsters were then exposed to cigarette smoke for the next 72 weeks. Four control groups received the same injections of NNK or trioctanoin but were treated by sham smoking. All groups treated with NNK had tumors of either the lung, nasal mucosa, and/or trachea. These tumors were not observed in hamsters injected with trioctanoin. These results demonstrate that even a single dose of NNK can induce respiratory tract tumors in Syrian golden hamsters. Smoke inhalation did not result in an increase in respiratory tract tumor incidence in most of the NNK treated groups.

Animals↗
PubMed1983

A study of betel quid carcinogenesis. 1. On the in vitro N-nitrosation of arecoline.

Betel quid chewing is strongly associated with cancer of the oral cavity. Extracts of betel quid are tumorigenic in the experimental animal, but thus far, not a single carcinogen has been detected in the tobacco free quid. This study is based on the hypothesis that during chewing, arecoline, the major alkaloid of the betel nut, gives rise to carcinogenic N-nitrosamines. In vitro experiments reported here have shown that N-nitrosation of arecoline leads to N-nitrosoguvacoline (NG), 3-(methylnitrosamino)propionitrile (MNPN) and 3-(methylnitrosoamino)propionaldehyde. Although, according to an earlier study. NG is most likely not carcinogenic, MNPN is suspected to be a relatively strong animal carcinogen based on bioassays with its lower homologue. The conditions prevailing in the oral cavity of betel quid chewers are likely to favor the formation of these three nitrosamines.

Alkaloids↗
PubMed1983

5-Methylchrysene metabolism in mouse epidermis in vivo, diol epoxide--DNA adduct persistence, and diol epoxide reactivity with DNA as potential factors influencing the predominance of 5-methylchrysene-1,2-diol-3,4-epoxide--DNA adducts in mouse epidermis.

5-Methylchrysene (5-MeC) can form two bay region dihydrodiol epoxides: 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (DE-I) which has the methyl group and the epoxide ring in the same bay region, and 7,8-dihydroxy-9,10-epoxy-7,8,10-tetrahydro-5-methylchrysene (DE-II). In a previous study, we observed that the ratio of DE-I:DNA adducts to DE-II:DNA adducts in mouse epidermis, 24 h after application of [3H]5-MeC metabolites was 2.7 to 1. To investigate the basis for this observation we have now studies: (i) the formation of [3H]5-MeC in mouse epidermis in vivo at various time intervals from 0.33 to 24 h; (ii) the persistence of DE-I:DNA adducts and DE-II:DNA adducts in mouse epidermis at 4-48 h after application of [3H]5-MeC; and (iii) the reactions of DE-I and DE-II with calf thymus DNA in vitro. In contrast to results obtained with mouse liver 9000 grams supernatant, the dihydrodiol precursors of DE-I and DE-II were present in equivalent quantities in mouse epidermis in vivo at every time point studied. The ratio of DE-I:DNA adducts to DE-II:DNA adducts in mouse epidermis was constant throughout the time period studied. However, the extent of formation of DE-I:DNA adducts was greater than that of DE-II:DNA adducts upon reaction of DE-I or DE-II with calf thymus DNA in vitro. These results suggest that differences in reactivity with DNA of DE-I and DE-II may bw responsible for the higher levels in mouse epidermis of DE-I:DNA adducts compared with DE-II:DNA adducts and provide a possible basis for the observed enhancing effect of a bay region methyl group on the carcinogenicity of polynuclear aromatic hydrocarbons.

Animals↗
PubMed1983

Identification of the metabolites of benzo[f]quinoline and benzo[h]quinoline formed by rat liver homogenate.

Benzo[f]quinoline and benzo[h]quinoline are widespread environmental pollutants which have been found to be mutagenic. The metabolism of benzo[f]quinoline and benzo[h]quinoline was investigated using a liver homogenate from Aroclor-pretreated rats. The metabolites of benzo[f]quinoline which were identified were 7,8-dihydroxy-7,8-dihydrobenzo[f]quinoline, 9,10-dihydroxy-9,10-dihydrobenzo[f]quinoline, 7-hydroxybenzo[f]quinoline, and benzo[f]quinoline-N-oxide. Metabolism studies on benzo[f]quinoline performed in the presence of the epoxide hydratase inhibitor, 3,3,3-trichloropropylene oxide, demonstrated that the formation of both of these dihydrodiols can be inhibited. The major metabolites of benzo[h]quinoline were identified as 5,6-dihydroxy-5,6-dihydrobenzo[h]quinoline and 7,8-dihydroxy-7,8-dihydrobenzo[h]quinoline. Benzo[h]quinoline-N-oxide was not detected as a metabolite. In the presence of an epoxide hydratase inhibitor, the major metabolites of benzo[h]quinoline were 5,6-epoxybenzo[h]quinoline and 7-hydroxybenzo[h]quinoline. The difference in the metabolism to N-oxides observed between benzo[h]quinoline and benzo[f]quinoline is consistent with previous observations in which sterically hindered aromatic ring nitrogen compounds such as benzo[h]quinoline are more resistant to N-oxide formation. The nitrogen atom of these aza-arenes with its lone pair of electrons has a significant influence on sites at which dihydrodiols are formed. The data suggest that the aromatic ring nitrogen of these azaphenanthrenes has an effect similar to that of a methyl substituent in directing their metabolic oxidation.

Animals↗
PubMed1983

On the metabolism of quinoline and isoquinoline: possible molecular basis for differences in biological activities.

Quinoline is a hepatocarcinogen in mice and rats, a mutagen in Salmonella typhimurium, and induces unscheduled DNA synthesis in primary cultures of rat hepatocytes. In contrast, isoquinoline has not been shown to be genotoxic. The metabolites of quinoline and isoquinoline, as formed in vitro with rat liver homogenate, were identified to investigate possible molecular bases for the differences in their biological activity. The ethyl acetate extractable metabolites of quinoline and isoquinoline were analyzed directly by high pressure liquid chromatography and, after silylation, by capillary gas chromatography. The major metabolite of quinoline was 5,6-dihydroxy-5,6-dihydroquinoline. Lesser amounts of 2- and 3-hydroxyquinoline and quinoline-N-oxide were also identified as metabolites. 1-, 4- and 5-Hydroxyiso-quinoline and isoquinoline-N-oxide were detected as metabolites of isoquinoline. 5,6-Dihydroxy-5,6-dihydroiso-quinoline was detected as only a minor metabolite. This difference in the extent to which these isomers are ultimately metabolized to dihydrodiols may be associated with their differences in biological activity. Quinoline, 4-methylquinoline and 7-methylquinoline were bioassayed as tumor initiators on the skin of Sencar mice. While 4-methylquinoline was at least as potent a tumor initiator as quinoline, 7-methylquinoline was not significantly tumorigenic in this assay. These data are consistent with the hypothesis that formation of the 5,6-epoxide of quinoline is associated with its metabolic activation to a tumorigen.

Animals↗
PubMed1983

Tumor promoters and cocarcinogens in tobacco carcinogenesis.

Cigarette smoke induces carcinoma of the larynx in Syrian golden hamsters and is active as a tumor promoter in hamsters pretreated with a low dose of a PAH, nitrosamine, or nitrosamide. These tumorigenic effects are only observed with total smoke, but not with the gas phase alone. This demonstrates that the tumorigenic agents reside primarily in the particulate phase. According to fractionation experiments, a number of four- and five-ring aromatic hydrocarbons serve as the major tumor initiators in tobacco smoke. Tumor promoters reside primarily in weakly polaric neutral subfractions and in the weakly acidic portion of the particulate matter and include certain unsaturated hydrocarbons and phenolic compounds. Cocarcinogenic activity is a characteristic feature of tobacco smoke and its particulates. Among the cocarcinogens formed during combustion are catechols and certain nontumorigenic aromatic hydrocarbons and terpenes. Nicotine may also serve as a cocarcinogen as is indicated by preliminary data. The action of tumor promoters and cocarcinogens in tobacco carcinogenesis, the precursors for tobacco smoke promoters and cocarcinogens, and methods for their reduction in smoke are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Reported cigarette smoke values: a closer look.

Effects of mechanical compression of the filter tips and of blocking the air channels of a special filter design on the smoke yields of seven brands of commercial filter cigarettes were investigated. In addition, the influence of these variables on actual uptake of smoke constituents by smokers was studied with four subjects. Compression of filter tips produced major increases in smoke yields for the cigarette which features a filter tip with four longitudinal air channels at its periphery. Blocking of these air channels increased tar yields by 51 per cent, nicotine by 69 per cent, and carbon monoxide by 147 per cent. Subjects who smoked the cigarette with this special filter design tended to smoke fewer cigarettes per day than when they smoked cigarettes with perforated filter tips, yet their plasma cotinine levels were significantly higher. Blood pressure and pulse rate were markedly elevated after first exposure to smoke from the special filter cigarette, as were plasma nicotine levels. These results point out that individuals inhale different quantities of smoke constituents from cigarettes with reportedly similar smoke yields according to Federal Trade Commission methods. A redefinition of "average" smoking parameters readjustment of standard laboratory methodology are suggested.

Carbon Monoxide↗