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At least 379 records · Page 21Linked to original sources
PubMed1977

Phenytoin inhibition: failure to inhibit periosteal responses to lathyrogen.

beta-Aminopropionitrile (BAPN) administered to rats has caused exostosis formation at sites of muscle attachment and also caused delay in the healing of soft tissue wounds and of bone fractures. Since phenytoin sodium has an opposite effect on wound healing, bone fractures, and the tensile strength of connective tissues, an experiment was performed to determine whether or not BAPN could produce periosteal exostoses in the presence of phenytoin. Rats that were given both BAPN and phenytoin produced similar exostoses as rats that were given BAPN alone. This indicates that phenytoin does not prevent inhibition of lysyl oxidase by BAPN, does not promote increased tensile strength of connective tissues in the presence of BAPN, and does not facilitate the detoxification of BAPN. Further, no evidence for an increased cellular response with phenytoin was observed. The mechanism by which phenytoin promotes wound healing is still unknown.

Aminopropionitrile↗
PubMed1966

Naturally occurring toxic factors in plants and animals used as food.

Toxic components of natural foodstuffs are discussed, with special reference to lathyrogens, pressor amines, azoxyglycosides, and labile sulfur compounds. The osteolathyrogen, gamma-glutamyl-beta-aminopropionitrile, in sweet pea (Lathyrus odoratus) seeds induces skeletal deformities and aortic rupture, probably by interfering with normal maturation of collagen fibres. Neurolathyrism in man may be caused by beta-N-oxalyl-L-alpha,beta-diaminopropionic acid, a neurotoxin recently identified in Lathyrus sativus seeds. Histamine, tyramine, noradrenaline, serotonin and other pressor amines occur in fruits and fermented foods such as bananas, pineapples, cheese and wine. Consumption of such foods by patients taking monoamine oxidase-inhibiting drugs (e.g. tranylcypromine) may produce serious hypertensive crises. Cycad nuts, widely used as human food in tropical and subtropical areas, contain a potent carcinogen, methyl azoxymethanol, which is more or less removed prior to use by leaching in water. Consumption of plants of the onion, cabbage and cress families introduces into the body such toxic chemicals as benzyl cyanide, goitrin and thiocyanates. The lachrymatory substance in onions is propenyl sulfenic acid.

Aminopropionitrile↗
PubMed1980

Experimentally induced cerebral aneurysms in rats: Part VI. Hypertension.

Cerebral aneurysms were induced in rats treated with unilateral ligation of the common carotid artery and hypertension produced by renal infarction with or without beta-aminopropionitrile, one of the lathyrogens. In this experiment, cerebral aneurysms developed more frequently than in the previous experiments in which hypertension induced by deoxycorticosterone and salt had been used. It was demonstrated that deoxycorticosterone was not essential to the development of the lesion. Regardless of its type, hypertension combined with carotid ligation played a primary role in the production of cerebral aneurysms in rats. Sodium chloride enhanced the systolic hypertension and thus increased the incidence of lesions. The role of hypertension in the development of cerebral aneurysms in humans is discussed.

Aminopropionitrile↗
PubMed1980

The importance of human intestinal diamine oxidase in the oxidation of histamine and/or putrescine.

Histamine, naturally methylated histamine and putrescine are good substrates for human intestinal diamine oxidase, N-Methyl-N-formylhydrazine, the constituent of the mashroom poison-gyromitrin is an inhibitor of human intestinal diamine oxidase. Burimamide inhibits more effectively mammalian intestinal diamine oxidases than pea seedling diamine oxidase, beta-aminopropionitrile is a better inhibitor of pea seedling enzyme than mammalian diamine oxidases. This inhibitory differences might be related to preference in histamine or putrescine oxidizing activity of these enzymes.

Amine Oxidase (Copper-Containing)↗
PubMed1984

Beta-substituted ethylamine derivatives as suicide inhibitors of lysyl oxidase.

Lysyl oxidase initiates the covalent cross-linking of elastin and collagen, converting lysyl residues in these proteins to peptidyl aldehyde residues. The present study explored structural and electron withdrawing features required to generate mechanism-based inhibitors of this enzyme with antifibrotic potential. It was found that the electron withdrawing nitrile moiety of beta-aminopropionitrile (BAPN), a naturally occurring syncatalytic inhibitor of lysyl oxidase, can be replaced by chlorine, bromine, or the nitro function to yield 2-haloamines or nitroethylamine compounds which also act as mechanism-based irreversible inhibitors of this enzyme. BAPN and 2-bromo- and 2-chloroethylamine exhibit similar KI values of 6-10 microM. However, the enzyme becomes irreversibly inactivated significantly faster by either of the 2-haloamines than by BAPN. 2-Nitroethylamine has by far the poorest affinity for the enzyme and inactivates much more slowly than the other amines of this series, consistent with interference with optimal enzyme-inhibitor interactions by the anionic nitro group. Unlike BAPN, 2-bromoethylamine is processed to a detectable aldehyde product upon incubation with enzyme, showing a partition ratio of 1.2 mol of acetaldehyde formed per mol of 2-bromo-ethylamine which becomes covalently incorporated in the enzyme. The results are consistent with the processing of 2-bromo-ethylamine to an enzyme-ethyleneamine Schiff base subject to hydrolysis to acetaldehyde or to covalent attack at carbon 2 by an enzyme nucleophile. Thus, beta-haloamines represent a new series of suicide inhibitors of lysyl oxidase which can inactivate the enzyme faster than BAPN and hence may have antifibrotic potential.

Amino Acid Oxidoreductases↗
PubMed1980

Evaluation of antifibrotic drugs in bleomycin-induced pulmonary fibrosis in hamsters.

Endotracheal administration of bleomycin to hamsters causes severe pulmonary fibrosis. We have examined the utility of this response as a model for the screening of pulmonary antifibrotic agents. The time course of collagen synthesis after bleomycin administration was examined in neutral salt soluble and insoluble fractions by in vitro incubation of minced lung with [14C] proline. Collagen synthesis increased to approximately 250% above control in both neutral salt soluble and insoluble collagen fractions by day 6 after bleomycin. Noncollagenous protein synthesis was also increased but to a lesser amount. The early rise in collagen synthesis leads to accumulation of collagen that can be biochemically quantitated within 1 week. This time course is advantageous for short-term testing of antifibrotic agents. In the present study, beta-aminopropionitrile, D-penicillamine, and p-aminobenzoic acid were examined. All three agents were found to reduce significantly the accumulation of neutral salt insoluble collagen in bleomycin-treated animals.

4-Aminobenzoic Acid↗
PubMed1981

Follow-up studies of workers with bladder neuropathy caused by exposure to dimethylaminopropionitrile.

Following a 1978 outbreak of bladder neuropathy among workers exposed to dimethyl-aminopropionitrile (DMAPN), follow-up studies were performed 2 a after the original epidemic to evaluate the persistence of symptoms among a small group of initially affected workers. Although the overall prevalence of urologic and neurological symptoms fell for the 11 persons interviewed, significantly high rates of persistent symptoms were seen. Of particular concern was the increase in the prevalence of symptoms of sexual dysfunction. Physical examination identified one individual with sensorimotor neuropathy which was initially detected 2 a earlier. Three individuals who had similar neuropathic findings in 1978 were normal 2 a later. Objective neurophysiological and urologic testing revealed evidence of persistent abnormalities in several workers, but most of the objective findings had improved over the 2-a period. The follow-up of residual effects of occupational exposure to neurotoxic substances is essential to the understanding of the course of occupational illnesses.

Adult↗
PubMed1980

Experimentally induced cerebral aneurysms in rats: Part V. Relation of hemodynamics in the circle of Willis to formation of aneurysms.

All the rats were made hypertensive and fed beta-aminopropionitrile. Among them, cerebral aneurysms were never found in rats without carotid ligation. In rats with ligation of one or both common carotid arteries, cerebral aneurysms developed on the vessels where hemodynamic stresses were apparently increased. The relationship of hemodynamics in the circle of Willis to the development of cerebral aneurysms is discussed, being compared with findings in spontaneous lesions in man.

Aminopropionitrile↗
PubMed1980

[Effect of pyridinol carbamate on long-term lathyrism and experimental atheroma in the rat. Histological and biochemical study].

Three-week-old rats were fed with Beta-aminopropionitrile (BAPN) with a normal or hyperlipidic diet. After a few weeks BAPN induced aortic elastic fibres disruption which as not worsened when the treatment was continued up the seven months. Adding a hyperlipidic diet produced atherosclerotic-like lesions. Pretreatment with Pyridinol Carbamate (PDC) whichever the diet used did not modify serum of aortic cholesterol levels. It decreased the severity of aortic lesions and delayed the onset of less severe atheromatous lesions. It seems that PDC increased the free/esterified aortic cholesterol ratio resulting in a better elimination of the aortic cholesterol.

Aminopropionitrile↗
PubMed1996

Formation of lamellar bone on the surface of woven bone is not prevented by BAPN.

To study the possible effect of collagen cross-link formation on the lamellar bone deposition, isolated mouse bone cells were transplanted in the syngeneic system and the formation of bone was followed in control and beta-aminopropionitrile (BAPN) treated animals. Woven and lamellar bone were distinguished by shape of bone lacunae, PAS reaction and Sirius red staining of collagen fibers. BAPN was administered in various doses either subcutaneously or in drinking water. Bone formed in BAPN treated animals contained both woven and lamellar bone in similar proportion as in controls. Thus, cross-linking of collagen seems to be unnecessary for lamellar bone deposition.

Aminopropionitrile↗
PubMedDate not supplied

Changes in alveolar capillary formation in growing rat lung by repeated injections of a lathyrogen.

We hypothesized that abnormal capillary formation, which might be associated with an alteration in extracellular malular matrix (ECM), occurs in the alveoli of growing rat lungs treated with beta-aminopropionitrile (beta APN), a lathyrogen that inhibits lysyl oxidase activity. On scanning electron microscopy, a corrosion cast of alveolar capillaries in lungs treated with beta APN appeared abnormal in configuration; transmission electron microscopy showed extensive morphological changes in interstitial cells and ECMs, including collagen, elastin, and presumably glycosaminoglycans and, in binding water (GBW). Morphometric data revealed an increase in GBW of up to 24.4%, a decrease in the amount of collagen fiber (44.5%), and a decrease in lipid-laden interstitial cells; however, the change in elastin was limited to morphological appearance. From these observations, we conclude that alterations in alveolar capillary formation are associate with extensive changes in ECMs, and that these changes in ECM components might also be involved in the abnormal alveolar formations induced by beta APN.

Aminopropionitrile↗
PubMed2000

Fully processed lysyl oxidase catalyst translocates from the extracellular space into nuclei of aortic smooth-muscle cells.

Lysyl oxidase (LO), a secreted protein, was recently identified within the nuclei of vascular smooth-muscle cells (SMC) and 3T3 fibroblasts. A possible pathway by which LO can enter cell nuclei was explored in the present study. SMC were incubated with purified 32-kDa bovine aorta LO that had been fluorescently labeled with rhodamine (TRITC-LO). TRITC-LO entered the cytosol and then rapidly concentrated within the nuclei of preconfluent cultures of these cells, whereas carbonic anhydrase, a protein of similar molecular weight and similarly labeled, did not enter the cells under these conditions. LO that had been reductively methylated at lysine residues with [(14)C]HCHO was also taken up into the cytosolic and nuclear compartments. Intracellular uptake and intracellular distribution were not altered by inhibiting LO activity with beta-aminopropionitrile. An excess of native LO but not of carbonic anhydrase competitively inhibited the uptake of the isotopically labeled enzyme. Thus, once secreted and proteolytically processed, mature LO can enter the cells and concentrate within nuclei in a manner that appears to be specific and independent of its catalytic activity.

3T3 Cells↗
PubMedDate not supplied

Collagen production by rat hepatocytes and sinusoidal cells in primary monolayer culture.

The cellular sources of collagen in normal rat liver have been examined. Hepatocytes and nonparenchymal (sinusoidal) cells were isolated and established in primary monolayer culture. These cells were incubated with radiolabeled proline in the presence of l-ascorbate and beta-aminopropionitrile. Nondialyzable material was prepared from the cell layer and the medium from each type of culture. The level of collagen accumulation was determined by measuring labeled hydroxyproline and sensitivity to purified bacterial collagenase. In hepatocytes, collagen represented 0.2% of both secreted and cell-associated labeled protein. In sinusoidal cells, collagen was 3.2% of secreted and 1.1% of cell-associated proteins. The total secreted labeled collagen, expressed per microgram of DNA, was similar in hepatocytes and sinusoidal cells. However cell-associated collagen in hepatocyte culture was approximately 10-fold that present in sinusoidal cells. These findings indicate that, while collagen formation is a relatively important function of sinusoidal cells, in normal liver the contribution of hepatocytes to total hepatic collagen accumulation may be substantial.

Animals↗
PubMedDate not supplied

Types of collagen synthesized by normal rat liver hepatocytes in primary culture.

Collagen formation is an important function of liver parenchymal cells that may be relevant to the pathogenesis of hepatic fibrosis. The types of collagen synthesized by cultured normal rat liver hepatocytes were examined. Cells isolated from adult rats by enzymatic dispersion of the liver were established in primary monolayer culture. Cells were then incubated with radiolabeled proline for 20 hr in the presence of ascorbate and the lathrogen beta-aminopropionitrile. Collagen secreted into the cell media was assessed separately from that in the cell layer. The greater proportion of newly synthesized collagen was associated with the cell layer. Collagen types were identified by ion exchange chromatography and by polyacrylamide gel electrophoresis. Types I, III, IV, and V collagen were present in both media and cell layer. Types III and V were the predominant types found. Very little Type I collagen was synthesized by these cultured normal hepatocytes. The percentages of Types I, III, IV, and V collagens, combining media and cell layer, were 6, 38, 19, and 36, respectively.

Animals↗
PubMed1995

Expression of lysyl oxidase from cDNA constructs in mammalian cells: the propeptide region is not essential to the folding and secretion of the functional enzyme.

Rat aortic lysyl oxidase cDNA was expressed under a metallothionein promoter in Chinese hamster ovary cells using a dihydrofolate reductase selection marker. One methotrexate-resistant cell line, LOD-06, generated by transfecting with full-length cDNA, yielded lysyl oxidase proteins consistent with the 50 kDa proenzyme and a 29 kDa mature catalyst. A second cell line, LOD32-2, was generated by transfection with a truncated cDNA lacking sequences which code for the bulk of the propeptide region. Both cell lines secreted apparently identical, 29 kDa forms of mature lysyl oxidase each of which catalyzed the deamination of human recombinant tropoelastin and alkylamines, consistent with the known specificity of lysyl oxidase. The secreted enzyme forms were inhibited by chemical inhibitors of lysyl oxidase activity, including beta-aminopropionitrile, phenylhydrazine, ethylenediamine, alpha, alpha'-dipyridyl, and diethyldithiocarbamate. Sensitivity to these agents is consistent with the presence of copper and carbonyl cofactors in the expressed enzymes, characteristic of lysyl oxidase from connective tissues. These results indicate the lack of essentiality of the deleted proprotein sequence for the proper folding, generation of catalytic function, and secretion of lysyl oxidase.

Amino Acid Sequence↗
PubMed1983

Elastin production by cultured calf pulmonary artery endothelial cells.

Calf pulmonary artery (CPA) endothelial cells synthesize and secrete soluble elastin when incubated in medium conditioned by arterial smooth muscle cells. Endothelial cell tropoelastin cross-reacts with antiserum to bovine ligamentum nuchae elastin and comigrates on SDS-PAGE with tropoelastins from fetal bovine ligamentum nuchae fibroblasts, aortic smooth muscle cells, and ear chondroblasts at an apparent molecular weight of 70,000. Endothelial cells synthesize only one-third as much elastin as these other cell types, however. Approximately 80% of the elastin synthesized by endothelial cells in confluent culture is released into the culture medium. The remaining 20% remains associated with the cell layer and is readily extractable with dilute acetic acid as un-cross-linked, 70,000-dalton tropoelastin. The addition of beta-aminopropionitrile to culture medium did not alter the ratio of tropoelastin in the medium and cell layer, suggesting that cross-linking of tropoelastin does not occur in culture. Immunofluorescent staining of confluent endothelial cell cultures with antielastin serum demonstrated elastin occurring as a web-like network of fine filaments extending throughout the extracellular space. The fibrous elastin was different in organization and distribution from fibers stained with antifibronectin serum, which were localized primarily beneath the cell layer and in regions of cell-cell contact. Extracellular matrix remaining after solubilization of cellular material with Triton X-100 stained positive for fibronectin, but not for elastin.

Animals↗
PubMed2004

A role for lysyl oxidase regulation in the control of normal collagen deposition in differentiating osteoblast cultures.

Differentiation of phenotypically normal osteoblast cultures leads to formation of a bone-like extracellular matrix in vitro. Maximum collagen synthesis occurs early in the life of these cultures, whereas insoluble collagen deposition occurs later and is accompanied by a diminished rate of collagen synthesis. The mechanisms that control collagen deposition seem likely to include regulation of extracellular collagen biosynthetic enzymes, but expression patterns of these enzymes in differentiating osteoblasts has received little attention. The present study determined the regulation of lysyl oxidase as a function of differentiation of phenotypically normal murine MC3T3-E1 cells at the level of RNA and protein expression and enzyme activity. In addition, the regulation of BMP-1/mTLD mRNA levels that encodes procollagen C-proteinases was assayed. The role of lysyl oxidase in controlling insoluble collagen accumulation was further investigated in inhibition studies utilizing beta-aminopropionitrile, a specific inhibitor of lysyl oxidase enzyme activity. Results indicate that lysyl oxidase is regulated as a function of differentiation of MC3T3-E1 cells, and that the maximum increase in lysyl oxidase activity precedes the most efficient phase of insoluble collagen accumulation. By contrast BMP-1/mTLD is more constitutively expressed. Inhibition of lysyl oxidase in these cultures increases the accumulation of abnormal collagen fibrils, as determined by solubility studies and by electron microscopy. Taken together, these data support that regulation of lysyl oxidase activity plays a key role in the control of collagen deposition by osteoblast cultures.

Alkaline Phosphatase↗