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Biomedical subjects

D Hoffmann

Publications and source records attributed to D Hoffmann.

At least 253 records · Page 14Linked to original sources
PubMed1985

Characterization of 5-hydroxytryptamine binding sites in the plasma membrane of pig blood platelets.

Plasma membranes were isolated from pig platelets after glycerol facilitated lysis by sucrose density gradient centrifugation. The purity of the membrane fraction was followed by electron microscopy, gel electrophoresis and analysis of acid phosphatase (EC 3.1.3.2) and phosphodiesterases (EC 3.1.4.1). (3H)5-Hydroxytryptamine ([3H]5-HT) was bound to two saturable binding sites of the membranes. The KD value for the high affinity sites was 0.85 nM and for the low affinity sites 0.48 microM. With the exception of tryptamines little or no (3H)5-HT was displaced by serotonin antagonists and uptake inhibitors suggesting another type of binding than that of 5-HT1. Apparently, enhancement of binding in the presence of Na+ was due to stimulation of an uptake process. Binding of (3H)ketanserin and (3H)LSD to pig platelet membranes showed the characteristics of 5-HT2 binding sites previously identified in rat brain. Since ketanserin inhibited 5-HT induced aggregation of pig platelets (IC50 = 14.2 nM), the ketanserin binding sites can be classified as 5-HT2 receptors. The functional properties of these binding sites and their density in pig platelets as compared with brain membranes may motivate studies on 5-HT2 receptors in pig platelets as models for those in nerve endings.

Animals↗
PubMed1985

Mutagens in human urine: effects of cigarette smoking and diet.

Human urine from smokers and nonsmokers on strictly controlled diets was assayed for mutagenic activity. Two distinct diets were employed in this study. Diet study A consisted of a high-meat, high-fat diet, observed for 5 days, followed by a vegan diet, adhered to for the next 5 days. The vegan diet contained no meat, fish, eggs, or dairy products. It was comprised of soy products, prepackaged vegan dinners, seeds, nuts, fruits, vegetables, beans and herbal teas. Diet study B consisted of 3 days on a typical western diet followed by a macrobiotic diet of grains and fresh vegetables for 5 days. Portions of 24-h urine samples were assayed in Salmonella typhimurium TA1538. The levels of urinary creatinine and cotinine were measured. Mutagenic activity was observed in the urine of most smokers. However, the levels of mutagens in the urine of light smokers were similar to those of nonsmokers. For both nonsmokers and smokers there was a significant increase in urine mutagenicity when volunteers were on the vegan diet. Several nonsmokers on the vegan diet in diet study A had pronounced mutagenic activity in their urine samples, in some instances at higher levels than that in the urine of smokers on a meat diet. In diet study B no clear differences were observed between the meat diet and the macrobiotic diet. In diet studies A and B the mutagenic potency of smokers' urine could not be correlated with cotinine levels alone or with urinary pH. These data suggest that dietary factors can play a dominant role in the mutagenicity of urine concentrates.

Adolescent↗
PubMed1985

Analysis of syn- and anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene -deoxyribonucleoside adducts by boronate chromatography.

The Servacel DHB (m-dihydroxyborylphenylaminoethyl cellulose) chromatographic procedure developed by Sawiki et al. (Cancer Res., 43,3212-3218, 1983) for analysis of 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adducts was applied to analyze syn- and anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (DE-I)-deoxyribonucleoside adducts. Identical elution conditions to whose developed for the DMBA adducts were employed. While the results were similar to those obtained in the DMBA system, some of the anti-DE-I-deoxyribonucleoside adducts eluted with the buffer system used for elution of syn-adducts. Complete resolution of the anti- and syn-adducts was obtained when modified elution conditions as developed by Pruess-Schwartz et al. (Cancer Res., 44, 4104-4110, 1984) for analysis of syn- and anti-7 alpha-8 beta-dihydroxy-9 beta, 10 beta-epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene--DNA adducts were applied. Based on this chromatographic procedure about 15% of the DE-I-deoxyribonucleoside adducts, formed in mouse skin DNA upon treatment with 5-[3H]methylchrysene (MeC), originated from syn-DE-I.

Animals↗
PubMed1985

Nicotine: a precursor for carcinogens.

Eric Boyland and collaborator demonstrated about 20 years ago that N'-nitrosonornicotine (NNN), a suspected smoke constituent, was a lung carcinogen in mice and that thiocyanate, a major detoxification product of the smoke component hydrogen cyanide, catalyzes the endogenous formation of nitrosamines. Also, Boyland presumed that the enzymatic conversion of nicotine may contribute to the carcinogenic potential of cigarette smoke via reactive intermediates. Chemical, biochemical and bioassay data gathered since these first observations, support the concept that the nicotine-derived NNN and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contribute significantly to the carcinogenic activity of snuff and cigarette smoke. Reactive metabolites of nicotine may also be carcinogenic factors. This hypothesis requires exploration.

Animals↗
PubMed1985

Cigarette smoking as a risk for cardiovascular disease. Part VI. Compensation with nicotine availability as a single variable.

In a biochemical investigation of human smoking behavior with filter cigarettes with high draw resistance that varied only in nicotine yield, we attempted to determine which nicotine levels provide desired nicotine intake with a minimum of physiologic and biochemical consequences. Twelve prescreened subjects were divided into two study groups and supplied with cigarettes that varied in nicotine delivery. Both groups were initially monitored while smoking their usual cigarette. At the following visit, smokers in group 1 received incremental increases and smokers in group 2 received incremental decreases in nicotine levels in assigned cigarettes. All subjects were monitored upon first exposure, after 1 week of acclimatization to each experimental cigarette, and upon return to their usual brands. Subjects in both groups were unable to compensate fully for their nicotine uptake from the lowest nicotine cigarette. In subjects in group 1, new nicotine baselines began to develop after 1 week of acclimatization to cigarettes containing 0.9 and 1.3 mg nicotine. New baseline nicotine levels were also noted in subjects receiving decreases in nicotine (group 2) after smoking the cigarette containing 1.3 mg nicotine for 1 week. Carboxyhemoglobin concentrations did not differ from those measured after the usual-brand cigarettes. Plasma cotinine concentrations increased as nicotine content per cigarette increased, except when subjects smoked a 1.3 mg nicotine cigarette. Plasma thiocyanate levels did not vary in either group. Systolic and diastolic blood pressures were generally not different from control values.

Adult↗
PubMed1985

Cadmium and nickel in mainstream particulates of cigarettes containing tobacco grown on a low-cadmium soil-sludge mixture.

Cigarettes were prepared from tobaccos grown in the greenhouse on a soil to which a low rate of a municipal sewage sludge was applied. The cigarettes were smoked by machine and the mainstream particulate fraction was analyzed for total cadmium and nickel content. Sludge-grown and control (soil-grown) tobaccos contained, respectively, 5.33 and 1.87 ppm of cadmium and 1.15 and 0.64 ppm of nickel. The average quantities of cadmium and nickel (ng/cigarette) found in the mainstream particulate fractions were, respectively, 220.5 and 78.5 for the sludge-grown and 147.4 and 72.6 for the control treatments. The difference between treatments was highly significant (p less than 0.001) for cadmium but not significant for nickel.

Cadmium↗
PubMed1985

Tumor-initiating activity, mutagenicity, and metabolism of methylated anthracenes.

Specific methylated derivatives of anthracene are mutagenic in S. typhimurium and have tumor-initiating activity on mouse skin. In this study, the mutagenic activities of 1-, 2-, and 9-methylanthracene, 2,9- and 9,10-dimethylanthracene, 2,9,-10-trimethylanthracene, 2,3,9,10-tetramethylanthracene, and the photo-oxide of 9,10-dimethylanthracene were determined in S. typhimurium TA98 and TA100. The relative tumor-initiating activities of these compounds were also evaluated. These bioassays indicate that increased mutagenic potency and tumor-initiating activity are associated with the presence of a methyl substituent at both the 9- and 10- position of anthracene. Metabolism studies suggest that the biological activity of specific methylated anthracenes may be related to the formation of a simple epoxide adjacent to a peri-methyl substituent.

Anthracenes↗
PubMed1985

On the analysis of 1-nitronaphthalene, 1-nitropyrene and 6-nitrochrysene in cigarette smoke.

A method was developed for the analysis of 1-nitronaphthalene, 1-nitropyrene, and 6-nitrochrysene in mainstream cigarette smoke, using [14C]1-nitronaphthalene, [14C]1-nitropyrene, and [14C]6-nitrochrysene as tracers and internal standards. Cigarette smoke condensate was collected and the appropriate fractions containing the labelled standards were obtained by a series of solvent partitions and column chromatography. Recovery of internal standards ranged from 60 to 70%. The fractions were analyzed by capillary gas chromatography with electron capture detection and by combined capillary gas chromatography-mass spectrometry. 1-Nitronaphthalene (less than 10 ng/cigarette), 1-nitropyrene (less than 10 ng/cigarette), and 6-nitrochrysene (less than 1 ng/cigarette) were not detected in the mainstream smoke of the University of Kentucky 1R1 cigarette, a US commercial 85 mm non-filter cigarette, or a French commercial 70 mm non-filter cigarette.

Chromatography, Gas↗
PubMed1985

On the pharmacokinetics of tobacco-specific N-nitrosamines in Fischer rats.

Methods were developed to determine the biological half-lives and rates of distribution and elimination of N'-nitrosonornicotine (NNN), N'-nitrosoanatabine (NAT), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in the F344 rat. The formation and persistence of an in vivo equilibrium between NNK and NNAL were also studied. The method consists of extraction and elution of the nitrosamines through a Clin-Elut column with ethyl acetate, followed by concentration and analysis by a gas chromatography-thermal energy analyzer. The biological half-lives for NNN and NAT were 184 and 540 min, those for NNK and NNAL ranged from 25 to 37 and 184 to 298 min, respectively. A relatively short biological half-life for the TSNA suggests a correlation with carcinogenic potency.

Animals↗
PubMed1985

Tumorigenicity of 5-methylchrysene dihydrodiols and dihydrodiol epoxides in newborn mice and on mouse skin.

5-Methylchrysene, (+/-)-trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene, (+/-)-trans-7,8-dihydro-7,8-dihydroxy-5-methylchrysene, (+/-)-trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (anti-DE-I), (+/-)-trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (syn-DE-I), and (+/-)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-methylchrysene (anti-DE-II) were tested for tumorigenicity in newborn mice and for tumor-initiating activity on mouse skin. In newborn mice, a total dose of 56 nmol of anti-DE-I induced 4.6 lung tumors/mouse and 1.2 liver tumors/mouse. These incidences were significantly higher than observed for any of the other metabolites, tested at equimolar doses. The results indicate that anti-DE-I, but not syn-DE-I or anti-DE-II, is a major ultimate carcinogen of 5-methylchrysene in the newborn mouse. Anti-DE-I was also more tumorigenic than anti-DE-II on mouse skin, inducing 4.4 tumors/mouse after an initiating dose of 100 nmol, compared to zero tumors per mouse induced by anti-DE-II. However, anti-DE-I was less tumorigenic on mouse skin than was its metabolic precursor, trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene or its parent hydrocarbon, 5-methylchrysene.

Animals↗
PubMed1985

Evaluation of the effects of cotinine and nicotine-N'-oxides on the development of tumors in rats initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide.

The effects of cotinine and nicotine-N'-oxides on tumor development in F344 rats initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide [(FANFT) CAS: 24554-26-5] were evaluated. When rats were 6 weeks old, FANFT in an agar diet was administered for a 6-week period. Subsequently, cotinine, trans-nicotine-N'-oxide, and a mixture of cis-nicotine-N'-oxide and trans-nicotine-N'-oxide in drinking water were given as promoters in concentrations of 0.1, 0.02, and 0.02%, respectively. These nicotine metabolites were offered ad libitum for 78 weeks. Control groups consisted of rats that received tap water with or without prior administration of FANFT. Cotinine, trans-nicotine-N'-oxide, and the mixture of cis- and trans-nicotine-N'-oxides were neither carcinogens nor promoters of urinary bladder tumors in rats initiated with FANFT. A reduced incidence of urinary bladder tumors was observed in FANFT-pretreated animals that also received a mixture of cis- and trans-nicotine-N'-oxides. FANFT administration increased the incidences of mesothelioma of the peritoneum and thyroid tumors. Tumor formation in the tongue and palate observed in FANFT-treated rats was not affected by administration of these nicotine metabolites. There was, however, a significant increase in the incidence of forestomach tumors in rats that were initiated with FANFT and subsequently received either trans-nicotine-N'-oxide or a mixture of cis- and trans-nicotine-N'-oxides.

Animals↗
PubMed1985

The effects of catechol on the urinary bladder of rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effect of catechol on the development of urinary bladder tumors in Fischer rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was studied. A solution of 0.05% catechol and 0.001% BBN was administered in the drinking water ad libitum for 78 weeks. The urinary bladders were then removed and examined microscopically. No statistically significant difference was observed between the experimental group receiving 0.001% BBN with 0.05% catechol and animals receiving 0.001% BBN alone with respect to the incidence of hyperplasia, papilloma, or carcinoma of the urinary bladder. Animals receiving 0.05% catechol alone in the drinking water had no macroscopic or microscopic lesions significantly different from those in control animals receiving tap water. Analyses of the urine of animals receiving catechol in their drinking water indicated that greater than 99% of the catechol present was in the form of either glucuronide or sulfate conjugates. In a second bioassay, the potential cocarcinogenicity of catechol, administered together with BBN, was explored by direct instillation into the urinary bladder. The development of calculi and possible infections of the urinary tract within all groups of treated animals suggests that this bioassay technique for cocarcinogenicity is of questionable value. These data show that catechol at the dose and mode of administration employed in this study did not affect the epithelium of the urinary bladder or enhance the carcinogenic activity of BBN.

Animals↗
PubMed1985

Rates of hydrolysis and extents of DNA binding of 5-methylchrysene dihydrodiol epoxides.

The rates of hydrolysis in the absence and presence of native and denatured DNA, and the extents of DNA binding of five dihydrodiol epoxides derived from 5-methylchrysene (5-MeC) and chrysene have been determined. The compounds studied were: trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC; trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-Mec; trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC; trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC; and trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene. In the absence of DNA, at pH 7 and 37 degrees C half-lives of trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC and trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC were similar, t 1/2 = 62 and 59 min, while trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC hydrolyzed faster than trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC, t 1/2 = 5.4 versus 17.5 min; trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene had the slowest rate of hydrolysis, t 1/2 = 104 min. Studies of the effects of native and denatured DNA on the rates of hydrolysis of the dihydrodiol epoxides indicated that native DNA remarkably accelerated these rates for all dihydrodiol epoxides, but the degree of acceleration varied for the different dihydrodiol epoxides. The acceleration of hydrolytic rates by native DNA relative to that by denatured DNA was correlated with the covalent binding of these dihydrodiol epoxides with DNA in vitro. The catalytic effect of DNA in enhancing the rates of hydrolysis of dihydrodiol epoxides and the relative extents of covalent binding of the dihydrodiol epoxides to DNA were in the following order: trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC greater than trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC greater than trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene greater than trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC greater than trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC. The results of this study suggest that physical interactions with DNA are important in determining the relative extents of binding of these dihydrodiol epoxides to DNA in vitro.

Chromatography, High Pressure Liquid↗
PubMed1985

New aspects of tobacco carcinogenesis.

In tobacco smoke, catechols represent a major group of cocarcinogens. Model studies have indicated that polyphenols and polysaccharides are two major groups of precursors for the catechol formation during smoking. Results from the application of BP together with catechol on mouse skin indicate that the detoxification path of BP metabolism is decreased and the formation of the BP-7,8-diol is increased in comparison to the metabolism pattern observed when BP is applied alone. It remains to be demonstrated that the increased BP-7,8-diol formation leads also to increased formation of BP-DNA adducts in epithelial tissues. The nicotine-derived N-nitrosamines represent a major group of carcinogens in chewing tobacco, snuff, and tobacco smoke. Their concentrations in processed tobacco and smoke exceed by far those of carcinogenic nitrosamines in other environmental materials. Whereas it has been shown that nicotine gives rise to NNN and NNK during tobacco chewing, the endogenous formation of these potent carcinogens upon smoke inhalation has so far not been demonstrated. However, the formation of N-nitrosoproline in cigarette smokers and snuff dippers proves that smoke and snuff have a measurable potential for the endogenous formation of carcinogenic nitrosamines. Finally, the data presented here indicate that the individuals subjected to passive smoke exposure under controlled conditions take up measurable amounts of particulate matter. The nicotine level in the saliva of nonsmokers reflect recent passive smoke exposure and levels of nicotine and cotinine in urine reflect the long-term exposure to smoke particulates. The indicators, measured in saliva and serum, make it clear that uptake of particulates due to passive smoke exposure corresponds only to a low percentage (less than 2%) of the particulates that represent the uptake of a 1 pack-a-day adult smoker. However, in special settings, such as in the exposure of infants to the smoke pollutants generated by their mothers, uptake of smoke constituents can reach levels which raise concerns as to possible long range toxic effects. A broader base of subjects and a wider range of pollution situations need to be tested in order to substantiate the significance of the dosimetry of uptake executed to date. Such measurements constitute an attempt at more accurate risk assessment for nonsmokers in smoke polluted environments.

Animals↗
PubMed1985

Lung cancer etiology: challenges of the future.

The 1982 Report of the Surgeon General of the U.S. Public Health Service concluded that "cigarette smoking is the major single cause of cancer mortality in the United States" and that "85 percent of lung cancer cases are due to smoking". Thus, major emphasis should be placed on school health education programs designed to prevent young people from smoking. Those students who are already cigarette smokers should be provided with an opportunity to attend smoking cessation courses with the hope that they stop. However, as long as society condones tobacco usage, millions of people will smoke, and millions of others will be involuntarily exposed to tobacco smoke. In this communication we have discussed the need for future research on the etiology of lung cancer. This includes the observation of a shift toward an increasing proportion of adenocarcinoma compared to squamous cell carcinoma of the lung in men, more detailed knowledge of the effects of macro- and micronutrients in the etiology of lung cancer, a clear delineation of the impact of tumor initiators, tumor promoters, and cocarcinogens in the development of lung cancer in cigarette smokers, and a study of the effects of the low-yield cigarette on the lung cancer risk of smokers. Finally, we reviewed the present knowledge as to the possible association of passive smoke exposure and lung cancer. Here we have placed major emphasis on the need for a close cooperation between epidemiologists and clinical biochemists in risk assessment.

Diet↗
PubMed1985

Analysis for nicotine and cotinine in hair to determine cigarette smoker status.

Noninvasive validation of cigarette smoking behavior is necessary for large population studies, especially with adolescents, where peer pressures can compromise self-report. Saliva and urine samples provide biological material for confirmation of recent nicotine intake by analysis for cotinine, the major metabolite of nicotine. However, detection of infrequent use of cigarettes can be missed in a single annual screen when participants have not smoked in the preceding week. We analyzed scalp hair from smokers and controls, to see whether hair could provide reliable samples for determining nicotine uptake. The amounts of nicotine and cotinine we detected in these samples correlated with individual smoking habits and exposures.

Cotinine↗