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PubMed1982

L-Arginine identified as an endogenous activator for soluble guanylate cyclase from neuroblastoma cells.

Guanylate cyclase in neuroblastoma N1E 115 cells was readily solubilized upon homogenization of the cells with hypotonic buffer. When the supernatant was passed through cation exchangers such as a Chelex 100 Na+ column, the guanylate cyclase activity in the effluent fraction decreased to 4-6% of the original supernatant. The addition of the acid extract of neuroblastoma cells or rat tissues to the effluent restored guanylate cyclase activity, indicating that the supernatant of neuroblastoma cells contained an acid-soluble endogenous activator for guanylate cyclase which was adsorbed on cation exchangers. The activator was purified from rat brain and identified as L-arginine by 13C- and 1H-NMR spectroscopy and paper partition chromatography. L-Arginine, at a concentration of 1-2 x 10(-5) M, stimulated guanylate cyclase activity in the effluent fraction 15-25-fold, whereas D-arginine and other basic L-amino acids were ineffective. Peptides that contained L-arginine at the NH2- or COOH-terminal also resulted in an activation of guanylate cyclase to the extent similar to that of L-arginine, while peptides that contained L-arginine inside the peptide chain failed to stimulate the activity. The activation of L-arginine seemed to operate by a mechanism similar to that induced by nitroso compounds.

Animals↗
PubMed1983

Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias, and neoplasms.

The dispersed neuroendocrine (NE) system is represented in the bronchopulmonary tract by the solitary neuroendocrine cells and the neuroepithelial bodies (NEBs). Immunohistochemically, neuron-specific enolase, serotonin, bombesin, and calcitonin are demonstrable in both components, whereas leu-enkephalin is demonstrable only in solitary NE cells. The precise function of and interplay between these two components under physiologic and pathologic conditions are not entirely clear. Current indications are that NEBs act as intrapulmonary chemoreceptors sensitive to hypoxia and hypercapnia, whereas solitary NE cells may have a paracrine, regulatory function. Even less clear is the possible role of solitary NE cells and NEBs in the processes associated with intrauterine and neonatal pulmonary growth and maturation. Various experimental manipulations have resulted in proliferation of solitary NE cells and NEBs. Of particular interest is the apparently selective proliferative effect on NEBs shown by several nitroso compounds. Diethylnitrosamine administration to hamsters for several weeks results in an increase in the number of NEBs and an increase in the number of cells per NEB. These hyperplastic NEBs express the same immunoreactive hormones as their normal counterparts. However, when NEB cells from diethylnitrosamine-treated hamsters are cultured in vitro a notable proportion of the resulting endocrine cells express ACTH immunoreactivity. Interestingly, the neoplasms that eventually develop in these hamsters are not comprised of NE cells. Studies on human bronchi from specimens resected for various types of neoplasms and for bronchiectasis with and without associated chronic obstructive pulmonary disease have revealed frequent hyperplasias of solitary NE cells and NEBs. In about 10% of the specimens, dysplastic aggregates of solitary NE cells and NEBs are found. Unexpected "microcarcinoids" and tumorlets are also seen. The mildly and moderately hyperplastic solitary NE cells and NEBs tend to express the hormones indigenous to the bronchi, whereas in the severely hyperplastic and dysplastic cells, "ectopic" hormones may also be expressed; the latter include predominantly ACTH and vasoactive intestinal polypeptide. A distinct hyperplasia of NEBs has been found in the lungs from individuals living at altitudes ranging from 3400 to 4300 meters; these changes may represent an adaptive response to chronic hypoxia parallel to the hyperplastic carotid paraganglia that may be found in the same type of population. Bronchopulmonary NE neoplasms comprise a spectrum that includes typical carcinoids, well-differentiated NE carcinomas, and NE carcinomas of intermediate and small cell types. Typical carcinoids are predominantly central, display little if any pleomorphism, are richly granulated by electron microscopy, and by immunohistochemistry express predominantly, although not exclusively, hormones indigenous to their site of origin.(ABSTRACT TRUNCATED AT 400 WORDS)

APUD Cells↗
PubMed1984

Regulation of soluble guanylate cyclase activity by porphyrins and metalloporphyrins.

Alterations of the chemical structure of protoporphyrin IX markedly altered the activation of soluble guanylate cyclase purified from bovine lung. Hydrophobic side chains at positions 2 and 4 and vicinal propionic acid residues at positions 6 and 7 of the porphyrin ring (protoporphyrin IX, mesoporphyrin IX) were essential for maximal enzyme activation (Ka = 7-8 nM; Vmax = 6-8 mumol of cGMP/min/mg). Substitution of hydrophobic with polar groups (hematoporphyrin IX, coproporphyrin III), or with hydrogen atoms ( deuteroporphyrin IX), and methylation of propionate residues resulted in decreased enzyme stimulation. Stimulatory porphyrins increased the Vmax and the apparent affinities of enzyme for MgGTP and uncomplexed Mg2+. An open central core in the porphyrin ring was essential for enzyme activation. The pyrrolic nitrogen adduct, N-phenylprotoporphyrin IX, was inhibitory and competitive with protoporphyrin IX (KI = 73 nM). Similarly, metalloporphyrins inhibited enzymatic activity and ferro-protoporphyrin IX (KI = 350 nM), zinc-protoporphyrin IX (KI = 50 nM) and manganese-protoporphyrin IX (KI = 9 nM) were competitive with protoporphyrin IX. Inhibitory porphyrins and metalloporphyrins also prevented enzyme activation by S-nitroso-N- acetylpenicillamine and NO. Guanylate cyclase reconstituted with such porphyrins required higher concentrations of protoporphyrin IX for further activation and were not activated by NO. Thus, porphyrins, metalloporphyrins, and NO appeared to interact at a common binding site on guanylate cyclase. This common site is likely that which normally binds heme and, therefore, NO-heme when the heme-containing enzyme is exposed to NO. Thus, NO and nitroso compounds may react with enzyme-bound heme to generate a modified porphyrin which structurally resembles protoporphyrin IX in its interaction with guanylate cyclase.

Adenosine Triphosphate↗
PubMed1980

Experimental pancreatic ductal (ductular) tumors.

Pancreatic ductal (ductular) tumors similar in morphological and biological characteristics to those in man can be induced in Syrian golden hamsters by specific nitroso compounds. The short latency period and high yield of these neoplasms and their possible selective induction make this model unique for investigating many aspects of this dismal human disease. Most of these neoplasms derive from ductular cells, including centroacinar cells and islet cell precursors, and only a few appear to arise from ductal epithelium. Tumors from both cell origins share various histological characteristics with relevant human tumors. Also, in analogy to the findings in man, we have seen mixed ductular-insular and ductular-acinar cell carcinomas. With regard to etiology, it is postulated that the similarity of the carcinogen molecule to sugar facilitates its uptake into the ductular cells (islet cell precursors). The histogenesis of tumors (which indicates an intimate relationship between the exocrine and endocrine pancreas) is described, tumor etiology is discussed and a system of classifying the induced tumors proposed.

Adenocarcinoma↗
PubMed1984

Enhanced repair of O6-alkylguanine in mammalian tissues.

N-nitroso compounds and related alkylating agents react with several nucleophilic sites in DNA. One of the products, O6-alkylguanine, may be responsible for the carcinogenic effects of such agents as it can mispair with thymine during DNA replication, thereby affecting the integrity of the genome and consequently the repair of this lesion could be an important determinant in carcinogenesis. The use of both in vivo and in vitro procedures for the assay of the activity of this repair system have shown that it can be enhanced in rat liver by treatment with a variety of agents while in other species, the system is not only less effective but does not appear to respond to such treatments. Differences in the capacity and inducibility of this repair system may be related to the susceptibility of different species to tumour induction by chronic administration of nitrosamines.

2-Acetylaminofluorene↗
PubMed1984

Use of aquarium fish, Danio rerio and Poecilia reticulata, as test species for evaluation of nitrosamine carcinogenicity.

The carcinogenic effects of various doses of dimethylnitrosamine (DMNA), diethylnitrosamine (DENA), and nitrosomorpholine (NM), as well as the results of varying temperature and length of exposure to these carcinogens, were studied in short-term (20-21 wk) experiments in aquarium fish (820 Danio rerio and 944 Poecilia reticulata). All nitroso compounds induced liver tumors (hepatocellular carcinomas and adenomas, cholangiomas, and cholangiocarcinomas) and esophageal papillomas. Exposure to NM also induced intestinal adenocarcinomas in D. rerio. At a conventional temperature (22 degrees +/- 1 degree C), tumors were induced in 76% of the D. rerio in an average of 13.8 weeks following an initial 8-week exposure to 100 ppm DMNA and in 22% of P. reticulata in an average of 10.9 weeks. The DENA exposure resulted in tumors in 61.5% of Danio by 15 weeks and in 29% of Poecilia in 15.5 weeks. Under the same conditions, 500 ppm NM induced tumors in 78% of the zebra fish in 15.6 weeks and in 75% of the guppies after 12.3 weeks. When exposure time was shortened to 2 weeks, the dosage was decreased, or if the temperature was reduced to 17 degrees +/- 1 degree C, the tumor incidence dropped and the latency increased. An increase in temperature to 27 degrees +/- 1 degree C resulted in a 72-89% tumor incidence and shortened the latency to 11.3-14.1 weeks. Thus the modulation of our experimental conditions to maximize tumor incidence and minimize mean latency permitted the use of the aquarium fish D. rerio and P. reticulata for the screening of carcinogenic nitrosamines.

Animals↗
PubMedDate not supplied

Spectrophotometric determination of pentaerythritol tetranitrate in tablets.

A sensitive spectrophotometric method is reported for the quantitative determination of pentaerythritol tetranitrate in tablets. The method is based on reduction of pentaerythritol tetranitrate with zinc and calcium chloride, and reaction of the nitroso compound thus formed with 1-naphthylamine in acidic medium. The reaction gives a purple product having an absorbance maximum at 545 nm. Beer's law is obeyed in the concentration range of 1-10 micrograms/mL of reaction mixture. The presence of meprobamate in tablets does not interfere with the proposed analytical determination.

Calcium Chloride↗
PubMed1984

Oxidation of ammonia and hydroxylamine to nitrate in the rat.

We have demonstrated that ammonia is oxidized to nitrate in the rat. Male Sprague-Dawley rats gavaged with 1 000 mumol 15N-ammonium chloride each day for five days were found to excrete low, but significant, amounts of excess 15N-nitrate in their urines on the five days of treatment and on the five subsequent days. We recovered a total of 0.28 +/- 0.03 mumol excess 15N-nitrate (mean +/- SE) per rat, which indicates that ammonia is converted to nitrate with a yield of about 0.0080%. 15N-Hydroxylamine was oxidized in the rat to 15N-nitrate with a yield of 4.7%, but oxidation of 15N-labeled glycine and L-glutamic acid to 15N-nitrate could not be detected. These results suggest that hydroxylamine, but not glycine or L-glutamic acid, may be an intermediate in the ammonia oxidation process. The injection of rats with Arochlor 1254 failed to stimulate nitrate synthesis, which indicates that the cytochrome P-450 drug metabolizing system is probably not involved in ammonia oxidation. Carbon tetrachloride, which causes hepatic lipid peroxidation, produced a small, but significant, increase in nitrate synthesis. Our results are consistent with the hypothesis that ammonia is oxidized in vivo by a non-enzymatic process involving reactive oxygen species. We estimate that a 215 g rat produces 3.0 mumol of nitrate per day by this process. The significance of our results to the problem of endogenous N-nitroso compound formation in man is discussed.

Ammonium Chloride↗
PubMed1984

Formation of nitrite in gastric juice of patients with various gastric disorders after ingestion of a standard dose of nitrate--a possible risk factor in gastric carcinogenesis.

Samples of fasting gastric juice (12-h fasting period) from patients with various upper gastrointestinal complaints and from healthy controls were collected by aspiration immediately before and 30, 90, and 240 min after ingestion of 200 mg nitrate in water. Nitrite concentration in the gastric juice of healthy controls remained essentially in a low concentration range throughout the whole sampling period (median values at various time points, 0.1-1.7 mg/L). Patients with gastric and duodenal ulcers and patients who had undergone proximal-gastral vagotomy did not show significant increases in gastric nitrite at any time when compared with healthy controls, using the Wilcoxon rank sum test. Patients with chronic atrophic gastritis and those who had undergone Billroth I or Billroth II gastric resection, however, showed significant increases in gastric nitrite, sometimes with high individual peaks: 80 mg/L in one patient with chronic atrophic gastritis, 50 mg/L in a Billroth I patient and 200 mg/L in a Billroth II patient. The results show that patients with chronic atrophic gastritis and patients who have undergone Billroth I and Billroth II gastrotomy not only have higher basal nitrite values in their gastric juice (12-h fasting) but also react with significantly higher increases in gastric nitrite to an oral dose of 200 mg nitrate, compared with healthy controls, ulcer patients and patients who have undergone proximal-gastral vagotomy. Higher nitrite levels might lead to an enhanced intragastric formation of N-nitroso compounds, and this might be relevant to the increased gastric cancer risk of these groups of patients.

Duodenal Ulcer↗
PubMedDate not supplied

High temperature purge and trap procedure for determining seven volatile N-nitrosamines in animal feed, using gas chromatography/thermal energy analyzer.

A rapid and sensitive procedure is described for determining 4 N-nitrosodialkylamines (dimethyl, diethyl, dipropyl, and dibutyl) and the N-nitroso analogs of piperidine, pyrrolidine, and morpholine in animal feed. The volatile N-nitrosamines were isolated by using a modified high temperature purge and trap apparatus designed for multiple sample cleanup. The feed sample was mixed with mineral oil and a nitrosation inhibitor, and the N-nitrosamines were purged onto a ThermoSorb/N cartridge, eluted with acetone-dichloromethane (1 + 1), and determined by gas chromatography, using a thermal energy analyzer. The effects of purge rate, purge time, and temperature on recovery are discussed. Feed samples spiked with 10, 50, and 200 ppb of the 7 N-nitroso compounds yielded recoveries ranging from 70 to 97%, with precision ranging from 1.3 to 5.4% and minimum detectable levels in the low parts-per-billion range.

Animal Feed↗
PubMed1978

Chemical models for possible nitrosamine artifact formation in environmental analysis.

Preliminary data concerning two different phenomena of potential importance to those studying the analysis and formation of environmental N-nitroso compounds are presented. First of all, we report that inorganic nitrite in the solid phase can serve as an effective nitrosating agent for solutions of amines in certain nonaqueous media. Secondly, we describe evidence suggesting that the appearance of nitrosamines as contaminants in deionized water (Cohen, 1977; Gough et al., 1977; Fiddler et al., 1977) might result at least partly from simple, acid-catalyzed nitrosation of the amine/ammonium functional groups on the anion exchange resins used in the demineralization process. Possible implications of both phenomena are discussed and potentially useful measures for their control are suggested.

Catalysis↗