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Biomedical subjects

D Hoffmann

Publications and source records attributed to D Hoffmann.

At least 199 records · Page 11Linked to original sources
PubMed1989

Elimination of cotinine from body fluids: disposition in smokers and nonsmokers.

We have evaluated differences in the elimination of cotinine, a major nicotine metabolite, in smokers who quit smoking and never-smokers who were exposed to environmental tobacco smoke (ETS) under controlled conditions. The mean biological half-life of cotinine in urine, collected from the nine smokers was 16.5 +/- 1.2 h, in never-smokers exposed to ETS, 27.3 +/- 1.9 h. Differences in the mode of uptake and absorption of nicotine and possible differences in nicotine metabolism may play roles in the clearance rate differences between smokers and nonsmokers.

Adult↗
PubMed1989

Mechanistic studies of tobacco carcinogenesis in mouse epidermis and lung tissues.

The particulate matter of tobacco smoke induces benign and malignant tumors in various animal tissues and species. The most widely used bioassay system for evaluating the carcinogenicity of tobacco tars is mouse skin. Mouse skin bioassays have led to the identification of the PAHs as the major tumor initiators, while showing that catechols are important cocarcinogens in tobacco smoke. Mechanistic studies suggest that catechol affects BaP metabolism and especially secondary oxidation reactions of this carcinogen and thus changes the proportion of BPDE-DNA adducts. Comparison of the disposition and metabolism of BaP and its ultimate carcinogenic derivative, anti-BPDE, in mouse epidermis demonstrates that the lower activity of BPDE relative to BaP in mouse skin is partially due to differences in penetration and trapping of BPDE within the epidermis, where it is protected from hydrolysis and reaction with intracellular macromolecules. Although screening for tumorigenicity on mouse skin is limited to the detection of certain classes of carcinogens and is not helpful for the evaluation of organ-specific carcinogens, mouse skin assays of cigarette smoke condensates have nevertheless served as valuable indicators of the tumorigenic potential of tobacco smoke for epithelial tissues.

Animals↗
PubMed1988

Cyanoethylation of DNA in vivo by 3-(methylnitrosamino)propionitrile, an Areca-derived carcinogen.

2-Cyanoethyldiazohydroxide is a likely product of metabolic alpha-hydroxylation of 3-(methylnitrosamino)propionitrile (MNPN). The reaction of 2-(N-carbethoxy-N-nitrosamino)propionitrile, a stable precursor of 2-cyanoethyldiazohydroxide, with deoxyguanosine, catalyzed by porcine liver esterase, was investigated. Two major deoxyguanosine adducts were produced. They were isolated by high-performance liquid chromatography and characterized by their UV spectra, mass spectra, and proton magnetic resonance spectra. On the basis of these spectral data, the structures of the two adducts were assigned as 7-(2-cyanoethyl)guanine and O6-(2-cyanoethyl)deoxyguanosine. The potential of MNPN to cyanoethylate DNA in F344 rats was evaluated by measuring 7-(2-cyanoethyl)guanine and O6-(2-cyanoethyl)guanine in the liver, nasal mucosa, and esophagus. The highest levels were detected in the nasal cavity, which is one of the major target organs for the carcinogenic effects of MNPN.

Animals↗
PubMed1988

Induction of lung and exocrine pancreas tumors in F344 rats by tobacco-specific and Areca-derived N-nitrosamines.

The tobacco-specific N-nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), as well as the Areca-derived N-nitrosoguvacoline (NG) were assayed for carcinogenicity in male F344 rats by lifetime administration in the drinking water. Groups of 30 to 80 rats were treated with 0.5 ppm, 1.0 ppm, or 5.0 ppm of NNK; 5.0 ppm of NNAL, 20 ppm of NG, a mixture of 20 ppm of NG and 1 ppm of NNK, and water only in the control group. The approximate total doses of the nitrosamines (mmol/kg of body weight) in these groups were: NNK, 0.073, 0.17, and 0.68; NNAL, 0.69; NG, 4.1; NG and NNK, 4.1 and 0.17. As in previous assays in which NNK was tested by s.c. injection, the lung was its principle target organ. Lung tumor incidences in the 0.5-, 1.0-, and 5.0-ppm groups were nine of 80, 20 of 80, and 27 of 30 compared to six of 80 in the control rats. This trend was significant, P less than 0.005. Significant incidences of nasal cavity and liver tumors were observed only in the rats treated with 5.0 ppm of NNK. In contrast to the results of the s.c. bioassays of NNK, tumors of the exocrine pancreas were observed in five of 80 and nine of 80 rats treated with 0.5 and 1.0 ppm. This trend was significant, P less than 0.025. This is the first example of pancreatic tumor induction by a constituent of tobacco smoke. It is also the first finding of duct-like carcinomas in the rat pancreas, including one tumor containing epidermoid, keratin-generating tissue. NNAL, the major metabolite of NNK, induced lung tumors in 26 of 30 rats and pancreatic tumors in eight of 30 rats. It appears to be the proximate pancreatic carcinogen of NNK. NG induced pancreatic tumors in four of 30 rats, P less than 0.05. This finding requires confirmation. The mixture of NG and NNK induced lung tumors in eleven of 30 rats. There were no apparent synergistic interactions of NG and NNK. The observation of benign and malignant tumors of the lung and pancreas of rats treated with the tobacco-specific nitrosamines NNK and NNAL is discussed in respect to the causal association between cigarette smoking and cancer of the lung and pancreas.

Animals↗
PubMed1988

Insect immunity. Purification and characterization of a family of novel inducible antibacterial proteins from immunized larvae of the dipteran Phormia terranovae and complete amino-acid sequence of the predominant member, diptericin A.

Injury or injection of live bacteria into third instar larvae of the dipteran insect Phormia terranovae results in the appearance in the haemolymph of at least five groups of heat-stable, more or less basic peptides with antibacterial activity against Escherichia coli. Three of these peptides have been purified. The amino acid sequence has been completely established for one of these and partially (first 40 residues from the N-terminus) for the two others. The sequences show marked homologies indicating that the three peptides belong to a common family. They are not related to other known antibacterial peptides from insects [lysozymes, cecropins (including sarcotoxin I) and attacins]. We propose the name of diptericins for this new family of antibiotic molecules.

Amino Acid Sequence↗
PubMed1988

Synthesis and kinetics of decomposition of 7-(2-cyanoethyl)guanine and O6-(2-cyanoethyl)guanine, markers for reaction of acrylonitrile and 3-(methylnitrosamino)propionitrile with DNA.

Acrylonitrile, a carcinogen in rodents, is used in the large-scale production of acrylic polymers. 3-(Methylnitrosamino)propionitrile, a potent carcinogen in Fisher rats, is an Areca-derived nitrosamine which has been found in the saliva of betel quid chewers. Upon metabolic activation, both of these carcinogens can react with DNA to form 7-(2-cyanoethyl)guanine and O6-(2-cyanoethyl)guanine. The latter has never been described. We have therefore synthesized this derivative by reacting 2-(N-carbethoxy-N-nitrosamino)propionitrile with deoxyguanosine.

Acrylonitrile↗
PubMed1988

Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke.

Tobacco-specific nitrosamines are a group of carcinogens that are present in tobacco and tobacco smoke. They are formed from nicotine and related tobacco alkaloids. Two of the nicotine-derived nitrosamines, NNK and NNN, are strong carcinogens in laboratory animals. They can induce tumors both locally and systemically. The induction of oral cavity tumors by a mixture of NNK and NNN, and the organospecificity of NNK for the lung are particularly noteworthy. The amounts of NNK and NNN in tobacco and tobacco smoke are high enough that their total estimated doses to long-term snuff-dippers or smokers are similar in magnitude to the total doses required to produce cancer in laboratory animals. These exposures thus represent an unacceptable risk to tobacco consumers, and possibly to non-smokers exposed for years to environmental tobacco smoke. The permission of such high levels of carcinogens in consumer products used by millions of people represents a major legislative failure. Indeed, the levels of tobacco-specific nitrosamines in tobacco are thousands of times higher than the amounts of other nitrosamines in consumer products that are regulated by government authorities. Although the role of tobacco-specific nitrosamines as causative factors in tobacco-related human cancers cannot be assessed with certainty because of the complexity of tobacco and tobacco smoke, several lines of evidence strongly indicate that they have a major role, especially in the causation of oral cancer in snuff-dippers. Epidemiologic studies have demonstrated that snuff-dipping causes oral cancer. NNK and NNN are quantitatively the most prevalent known carcinogens in snuff, and they induce oral tumors when applied to the rat oral cavity. A role for NNK in the induction of lung cancer by tobacco smoke is likely because of its organospecificity for the lung. Tobacco-specific nitrosamines may also be involved in the etiology of tobacco-related cancers of the esophagus, nasal cavity, and pancreas. Because they are derived from nicotine, and therefore should be associated only with tobacco, tobacco smoke and other nicotine-containing products, tobacco-specific nitrosamines as well as their metabolites and macromolecular adducts should be ideal markers for assessing human exposure to, and metabolic activation of, tobacco smoke carcinogens. Ongoing research has demonstrated the formation of globin and DNA adducts of NNK and NNN in experimental animals. Sensitive methods for the detection and quantitation of these adducts in humans would provide an approach to assessing individual risk for tobacco-related cancers.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗
PubMed1988

Immunoglobulins and immunoglobulin-containing cells in the reproductive tracts of rams naturally infected with Brucella ovis.

Thirteen rams with serological evidence of Brucella ovis exposure (CFT of 1:8 or greater), but with no or only mild epididymitis, were selected from a ram flock. Serum, semen, preputial washings and fluids from the accessory sex glands (ASGF) and testis and epididymis (TEF) were examined and immunoglobulin (Ig) concentrations estimated. Genital tissues were examined histologically and the percentages of class specific immunoglobulin containing cells (ICC) determined. Eleven of these rams had histological evidence of active inflammation consistent with B. ovis infection; the organisam was cultured from the semen of 7. IgA concentration was high in semen (mean +/- standard deviation of 5.03 +/- 1.78 mg/ml) and ASGF (9.18 +/- 7.28 mg/ml). These levels were much higher than those recorded in noninfected rams. IgA concentration was low in serum (0.78 +/- 0.55 mg/ml) and TEF (0.59 +/- 0.78 mg/ml). The concentrations of IgG1, IgG2 and IgM were low in all genital fluids sampled and not significantly different from those recorded in noninfected rams. This indicated that infection with B. ovis results in a pronounced IgA response in secretions, mostly from the accessory sex glands. Examinations of ICC, however, revealed that the plasma cell infiltrates of the epididymis, vas deferens, ampulla and seminal vesicle were predominantly IgG-containing (92.4, 97.2, 79.4 and 91.9% respectively). Fewer IgM-containing cells were scattered throughout these tissues, constituting 3.9, 6.3, 0.3 and 6.5% of all ICC, respectively. IgA-containing cells were most frequently seen in the ampulla (9.6% of ICC) where they were located directly beneath the epithelium, suggesting the ampulla as the most prominant location for the local production of IgA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Pathology of varicocele in the ram.

A total of 40 mature or aged rams with spontaneous varicocele detected by scrotal palpation were subjected to detailed necropsy examination. Varicocele was bilateral in 22 rams or was located on the left or right sides only, in 8 and 10 rams, respectively. This distribution contrasted with varicocele in man in which the left side is involved in 70 to 100% of cases. Mean sizes of varicoceles in mm (length x diameter) were 117 x 46 and 104 x 45 for the left and right sides, respectively, and they were located high in the pampiniform plexus, approximately 100 mm from the dorsal pole of the corresponding testis. All varicoceles were thrombosed. Changes associated with large varicoceles included testicular mineralisation and occluding thrombosis of testicular vessels. Total testis weight-bodyweight ratio in rams with varicocele (5.8 to 6.4 x 10(-3] was significantly less (P less than 0.05) than in normal (control) rams from the same flocks (7.9 x 10(-3] suggesting that some degree of testicular atrophy resulted from presence of a varicocele.

Animals↗
PubMed1988

Immunoglobulins and immunoglobulin-containing cells in the reproductive tract of normal rams.

The levels of the immunoglobulins IgA, IgG1, IgG2, and IgM were measured in serum and fluid from various locations in the reproductive tract of normal rams. These fluids included semen, preputial washings, and fluid from the accessory sex glands (ASG), vasa deferens, rete testes, and tissue fluid from the seminal vesicles, bulbourethral glands, epididymal tails and efferent ducts. In addition, the prevalence of specific Ig-containing cells (ICC) was measured in sections of formalin fixed tissues stained by an indirect peroxidase-antiperoxidase labelling technique. Mean IgA levels in semen (1.23 mg/ml) and ASG fluid (0.46 mg/ml), were higher than in serum (0.19 mg/ml) and were at levels higher than IgG1 or IgG2 levels in semen, ASG fluid, and preputial washings, thus confirming the existence of a local immune system primarily in the ASG of ram genitalia. Relatively low concentrations of IgA and IgG in other genital fluids and IgG levels in these fluids were consistent with diffusion from serum. The relatively high prevalence of IgA-containing cells in bulbourethral (56% of all ICC) and prostate (49%) glands confirmed these tissues as major sites of local Ig production. ICC were also found in large numbers beneath pelvic urethral and preputial epithelia, but these were predominantly IgG-containing (88 and 72% respectively).

Animals↗
PubMed1988

Approaches to the development of assays for interaction of tobacco-specific nitrosamines with haemoglobin and DNA.

The tobacco-specific, nicotine-derived nitrosamines 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are among the most important carcinogens in tobacco and tobacco smoke. Treatment of Fischer 344 rats with these carcinogens resulted in alkylation of haemoglobin and DNA by the 4-(3-pyridyl)-4-oxobutyl group formed during their metabolism. This alkyl group can be detached from globin or DNA under mild hydrolytic conditions as 4-hydroxy-1-(3-pyridyl)-1-butanone, which appears to be a potentially useful dosimeter for human exposure to, and activation of, tobacco-specific nitrosamines.

Animals↗