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  • 1
    ISSN: 1432-1912
    Keywords: Key words NNK ; Nicotine ; Cotinine ; Starvation ; Metabolism ; Lung ; Liver ; Perfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The scope of the present study was to investigate whether nicotine or cotinine will affect the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated perfused rat lungs and livers and to study the effect of starvation on pulmonary metabolism of NNK. NNK metabolism was investigated in isolated perfused liver and lung of male F344 rats perfused with 35 nM [5-3H]NNK in presence of a 1400-fold excess of the main tobacco alkaloid nicotine and its metabolite cotinine. In perfused rat livers, nicotine and cotinine inhibited NNK elimination and metabolism and led to a substantial increase of elimination half-life from 14.6 min in controls to 25.5 min after nicotine and 36.6 min after cotinine co-administration, respectively. In parallel, the pattern of NNK metabolites was changed by nicotine and cotinine. The pathway of α-hydroxylation representing the metabolic activation of NNK was decreased to 77% and 85% of control values, whereas N-oxidation of NNK and glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased 2.6- and 1.2-fold in presence of nicotine and cotinine, respectively. When isolated rat lungs were perfused with 35 nM NNK for 3 h neither the elimination nor the pattern of metabolites were substantially affected due to co-administration of 50 μM nicotine or cotinine. Cytochrome P450 2E1 is known to participate in the activation of NNK and can be induced by starvation. However, isolated rat lungs from male Sprague Dawley rats perfused with [1-14C]NNK at about 2 μM for 3 h, revealed only small differences in pulmonary elimination and pattern of NNK metabolites between fed and starved animals. These results suggest that nicotine and its main metabolite cotinine inhibit the metabolic activation of NNK predominantly in the liver whereas activation in lung, a main target organ of NNK induced carcinogenesis, remained almost unaffected.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Archives of toxicology 65 (1991), S. 429-432 
    ISSN: 1432-0738
    Keywords: Copper accumulation ; Kidney ; Liver ; Small intestine ; TCDD ; Trace metals
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Recently, acutely toxic doses of the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been reported to affect the hepatic distribution of essential metals in the rat. However, the reduced food intake by TCDD was not taken into account. Therefore, metal concentrations were determined in different rat tissues at the end of a toxicity study with TCDD in which a pair-fed control group was introduced. Male Sprague-Dawley ats received a single i.p. injection of corn oil/acetone with or without TCDD at 125 μg/kg. Controls and TCDD-treated rats were fed ad libitum; additionally, pair-fed controls received the amount of food consumed by their TCDD-treated partners 1 day before. Twenty-one days after dosing rats were killed and samples of liver, kidney and jejunum were taken for the analysis of Ca, Cu, Fe, Mg, Mn, and Zn. After acid digestion of the tissues metals were determined by atomic emission spectrometry (AES). The most outstanding effect of TCDD treatment was an increase of the copper levels in the kidney (4-fold, versus pair-fed controls) and in the liver (〉2-fold, versus pair-fed controls). Other metals were mainly affected by the reduced food intake only. Since Cu represents a trace metal the homeostasis of which depends on its biliary excretion and since TCDD is known to impair biliary flow and excretion, an impaired biliary excretion of Cu by TCDD is suggested as the causal mechanism.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0738
    Keywords: Dibutylnitrosamine ; Metabolism ; Human ; Rat ; Liver ; intestine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The metabolism of the bladder carcinogen N-nitroso-di-n-butylamine (NDBA) was studied in microsomal preparations of tissues of patients of both sexes, aged 59–69 years undergoing abdominal surgery. Samples of liver, ileum, and colon were of normal histological appearance. For comparison, samples of rat liver and small intestinal mucosa microsomes were included in the study. Using 1-14C-labeled NDBA, the biotransformation to hydroxylation products retaining the nitroso group, NDBA-2-OH, NDBA-3-OH, and NDBA-4-OH, respectively, was investigated by reversed phase HPLC. In order to separate these metabolites, pooled samples were analysed by normal phase HPLC. The rate of hydroxylation of NDBA was found to be 5.5 times higher in rat liver microsomes compared to those from human liver (2.86±0.29 vs 0.52±0.03 nM x min−1 x mg−1). NDBA-3-OH proved to be the major metabolite formed (〉80% of total metabolites). The metabolism of NDBA was low but detectable in seven out of nine specimens of human gut, 0.1–0.5 nM x mg−1 in 1 h of incubation, and of the same order of magnitude in rat intestinal tissue (0.4–0.6 nM x mg−1).
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 357 (1998), S. 336-343 
    ISSN: 1432-1912
    Keywords: Key words NNK ; Elimination kinetics ; Metabolism ; Perfusion ; Lung ; Liver ; Rat ; N-oxide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a strong lung carcinogen in all species tested. To elicit its tumorigenic effects NNK requires metabolic activation which is supposed to take place via α-hydroxylation, whereas N-oxidation is suggested to be a detoxification pathway. The differences in the organ specific metabolism of NNK may be crucial for the organotropy in NNK-induced carcinogenesis. Therefore, metabolism of NNK was investigated in the target organ lung and in liver of Fischer 344 (F344) rats using the model of isolated perfused organs. High activity to metabolize 35 nM [5-3H]NNK was observed in both perfused organs. NNK was eliminated by liver substantially faster (clearance 6.9 ± 1.6 ml/min, half-life 14.6 ± 1.2 min) than by lung (clearance 2.1 ± 0.5 ml/min, half-life 47.9 ± 7.4 min). When the clearance is calculated for a gram of organ or for metabolically active cell forms, the risk with respect to carcinogenic mechanisms was higher in lung than in liver. The metabolism of NNK in liver yielded the two products of NNK α-hydroxylation, the 4-oxo-4-(3-pyridyl)-butyric acid (keto acid) and 4-hydroxy-4-(3-pyridyl)-butyric acid (hydroxy acid). In lung, the major metabolite of NNK was 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide). Substantial amounts of metabolites formed from methyl hydroxylation of NNK, which is one of the two possible pathways of α-hydroxylation, were detected in lung but not in liver perfusion. Formation of these metabolites (4-oxo-4-(3-pyridyl)-butanol (keto alcohol), and 4-hydroxy-4-(3-pyridyl)-butanol (diol) can give rise to pyridyloxobutylating of DNA. When isolated rat livers were perfused with 150 μM NNK, equal to a dosage which is sufficient to induce liver tumors in rat, glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased when compared to the concentration of 35 nM NNK. Nevertheless, the main part of NNK was also transformed via α-hydroxylation for this high concentration of NNK.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    European archives of oto-rhino-laryngology and head & neck 221 (1978), S. 221-225 
    ISSN: 1434-4726
    Keywords: Larynx ; Pachydermie ; Hormonbehandlung ; Antiandrogene ; Cyproteronazetat ; Larynx ; Pachydermia laryngis ; Hormonetherapy ; Antiandrogens ; Cyproterone-acetate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary First clinical experiences with the anti-androgenic drug cyproteroneacetate in treatment of pachydermia laryngis are reported in eleven male and female patients. This endocrine therapy led to complete healing in four and to marked improvement in six patients. One did not respond. Evaluation of the endocrine state of these patients showed imbalance in the androgen/estrogen equilibrium. As the larynx constitutes a secondary sex characteristic and an endocrine target organ, the significance of endocrine factors for pathogenesis and therapy of epithelial changes on the vocal cords is discussed.
    Notes: Zusammenfassung Es wird über erste klinische Erfahrungen in der Behandlung der Pachydermia laryngis mit dem Testosteronantagonisten Cyproteronazetat an elf Patienten beiderlei Geschlechts berichtet. Diese neuartige Therapie führte in vier Fällen zu vollständiger Heilung, bei sechs Patienten zu wesentlicher Besserung und blieb in einem Fall erfolglos! Hormonbestimmungen deckten Störungen im Androgen/Östrogen-Gleichgewicht auf. Die Bedeutung endokriner Faktoren für die Pathogenese und die Therapie von Epithelveränderungen im Larynx als einem sekundären Geschlechtsmerkmal wird diskutiert.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    European archives of oto-rhino-laryngology and head & neck 215 (1977), S. 75-79 
    ISSN: 1434-4726
    Keywords: Larynx ; Pachydermia laryngis ; Anti-androgens ; Cyproteroneacetate ; Larynx ; Pachydermie ; Anti-Androgene ; Cyproteronazetat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Es wird über eine 56jährige Patientin mit Pachydermia laryngis und Hirsutismus berichtet, die erfolgreich mit dem Testosteron-Antagonisten Cyproteronacetat behandelt werden konnte. An Hand dieses Falles wird die Bedeutung androgener Hormone für die Genese von Epithelveränderungen am weiblichen Kehlkopf unterstrichen und die Anwendung antiandrogener Substanzen als neuartige therapeutische Möglichkeit diskutiert.
    Notes: Summary Case-report about a 56 year old white female patient with pachydermia laryngis and hirsutism, successfully treated with cyproterone-acetate, a testosterone antagonist. The significance of androgenic hormones for the development of epithelial changes in the female larynx is emphasized. The administration of antiandrogenic substances as a new therapeutic measure is discussed.
    Type of Medium: Electronic Resource
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