scholarly journals The inhibition of lysyl oxidase in vivo by isoniazid and its reversal by pyridoxal. Effect on collagen cross-linking in the chick embryo

1984 ◽  
Vol 221 (3) ◽  
pp. 837-843 ◽  
Author(s):  
M J Carrington ◽  
T A Bird ◽  
C I Levene
Keyword(s):  
Pyridoxal Phosphate ◽  
Isonicotinic Acid ◽  
Lysyl Oxidase ◽  
Acid Hydrazide ◽  
Chick Embryos ◽  
Cross Link ◽  
Irreversible Inhibitor ◽  
Link Formation

Isonicotinic acid hydrazide (isoniazid) causes a large increase in the salt-solubility of collagen when injected into chick embryos; this change is accompanied by the inactivation of lysyl oxidase (EC 1.4.3.13), the enzyme responsible for initiating cross-link formation in collagen and elastin. In addition, isoniazid markedly decreases the liver content of pyridoxal phosphate. The depletion of pyridoxal phosphate takes approx. 6 h, whereas the inhibition of lysyl oxidase and the increase in collagen solubility occur more slowly. A reversal of these effects of isoniazid can be produced by the subsequent injection of a stoichiometric amount of pyridoxal, supporting the role of pyridoxal as a cofactor for lysyl oxidase. Treatment of chick embryos with beta-aminopropionitrile, an irreversible inhibitor of lysyl oxidase, causes an inhibition of the enzyme, which begins to recover within 24 h but which is not affected by the administration of pyridoxal; with isoniazid inhibition, however, lysyl oxidase activity does not show any sign of recovery by 48 h. It is proposed that isoniazid may cause the inhibition of lysyl oxidase by competing for its obligatory cofactor, pyridoxal phosphate. The potential clinical implications in the therapeutic control of fibrosis are briefly discussed.

scholarly journals Lysyl oxidase activity and elastin/glycosaminoglycan interactions in growing chick and rat aortas.

1987 ◽  
Vol 105 (3) ◽  
pp. 1463-1469 ◽  
Author(s):  
C Fornieri ◽  
M Baccarani-Contri ◽  
D Quaglino ◽  
I Pasquali-Ronchetti
Keyword(s):  
Hydrophobic Interactions ◽  
Isonicotinic Acid ◽  
Lysyl Oxidase ◽  
Acid Hydrazide ◽  
Elastic Fibers ◽  
Amino Groups ◽  
Lysine Residues ◽  
Oxidase Inhibition

Hydrophobic tropoelastin molecules aggregate in vitro in physiological conditions and form fibers very similar to natural ones (Bressan, G. M., I. Pasquali Ronchetti, C. Fornieri, F. Mattioli, I. Castellani, and D. Volpin, 1986, J. Ultrastruct. Molec. Struct. Res., 94:209-216). Similar hydrophobic interactions might be operative in in vivo fibrogenesis. Data are presented suggesting that matrix glycosaminoglycans (GAGs) prevent spontaneous tropoelastin aggregation in vivo, at least up to the deamination of lysine residues on tropoelastin by matrix lysyl oxidase. Lysyl oxidase inhibitors beta-aminopropionitrile, aminoacetonitrile, semicarbazide, and isonicotinic acid hydrazide were given to newborn chicks, to chick embryos, and to newborn rats, and the ultrastructural alterations of the aortic elastic fibers were analyzed and compared with the extent of the enzyme inhibition. When inhibition was greater than 65% all chemicals induced alterations of elastic fibers in the form of lateral aggregates of elastin, which were always permeated by cytochemically and immunologically recognizable GAGs. The number and size of the abnormal elastin/GAGs aggregates were proportional to the extent of lysyl oxidase inhibition. The phenomenon was independent of the animal species. All data suggest that, upon inhibition of lysyl oxidase, matrix GAGs remain among elastin molecules during fibrogenesis by binding to positively charged amino groups on elastin. Newly synthesized and secreted tropoelastin has the highest number of free epsilon amino groups, and, therefore, the highest capability of binding to GAGs. These polyanions, by virtue of their great hydration and dispersing power, could prevent random spontaneous aggregation of hydrophobic tropoelastin in the extracellular space.

scholarly journals Evidence for the role of vitamin B-6 as a cofactor of lysyl oxidase

1977 ◽  
Vol 167 (2) ◽  
pp. 463-467 ◽  
Author(s):  
J C Murray ◽  
C I Levene
Keyword(s):  
Enzyme Activity ◽  
Isonicotinic Acid ◽  
Lysyl Oxidase ◽  
Acid Hydrazide ◽  
Single Peak ◽  
Partial Purification ◽  
Vitamin B ◽  
Epiphysial Cartilage

At 24 h after injection of 16-day chick embryos with [C-3H]pyridoxine hydrochloride, some of this label appears in the epiphysial cartilage. Over 35% of this radioactivity appears in the form of [G-3H]pyridoxal and a further 30% as other vitamin B-6 compounds. Partial purification of lysyl oxidase from the labelled epiphysial cartilage reveals a single peak of radioactivity coinciding with a single peak of enzyme activity. On dialysis against phosphate-buffered saline, 75% of this radioactivity is found to be non-diffusible. After incubation with isonicotinic acid hydrazide, a carbonyl reagent that appears to inhibit lysyl oxidase both in vivo and in vitro, a further 70% of the radioactivity is lost, with a roughly corresponding loss of enzyme activity. It is suggested that a form of vitamin B-6 is required as a cofactor of lysyl oxidase, and that this may have important implications in terms of connective-tissue metabolism.

scholarly journals The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

2021 ◽  
Author(s):  
Marlaina R. Stocco ◽  
Ahmed A. El-Sherbeni ◽  
Bin Zhao ◽  
Maria Novalen ◽  
Rachel F. Tyndale
Keyword(s):  
Neurotransmitter Release ◽  
Behavioral Sensitization ◽  
Serotonin Release ◽  
Striatal Dopamine ◽  
Irreversible Inhibitor ◽  
Drug Concentrations ◽  
Metabolite Concentrations ◽  
The Brain

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

THE ROLE OF RIBOFLAVIN IN MONOAMINE OXIDASE ACTIVITY

1963 ◽  
Vol 41 (1) ◽  
pp. 57-64 ◽  
Author(s):  
M. H. Wiseman-Distler ◽  
T. L. Sourkes
Keyword(s):  
Monoamine Oxidase ◽  
De Novo ◽  
Intraperitoneal Administration ◽  
Enzymatic System ◽  
Irreversible Inhibitor ◽  
Riboflavin Deficiency ◽  
Deficient Diet ◽  
Hydroxyindoleacetic Acid

The role of riboflavin in the activity of monoamine oxidase (MAO) was investigated by omitting the vitamin from the diet of rats which were further treated with iproniazid, an irreversible inhibitor of the enzyme. The rate of recovery from the inhibition, presumably reflecting de novo synthesis of the enzyme, was estimated by measuring the excretion of the acidic metabolites formed after intraperitoneal administration of serotonin (5 HT) and dopamine. Consumption of the deficient diet did not impair the action of MAO on these amines. After injection of iproniazid, return to control levels of MAO activity was slower when measured by the oxidation of dopamine than of 5 HT; there was a small but significant effect of riboflavin deficiency upon the conversion of 5 HT to 5-hydroxyindoleacetic acid. This was probably due to enhanced inhibition of MAO observed in deficient rats, an effect that was also obtained when inhibitors other than iproniazid were used in vivo. Similarly, disappearance of 5 HT during incubation with a supernatant prepared from liver of deficient rats was also affected to a greater extent by these inhibitors than when the enzymatic system was prepared from control livers. This finding suggests that riboflavin deficiency renders MAO more susceptible to inhibition.

The roles of node regression and elongation of the area pellucida in the formation of somites in avian embryos

Development ◽  
1984 ◽  
Vol 81 (1) ◽  
pp. 75-92
Author(s):  
Claudio D. Stern ◽  
Ruth Bellairs
Keyword(s):  
Chick Embryos ◽  
Local Conditions ◽  
Avian Embryos ◽  
Somite Formation ◽  
Mechanical Tensions ◽  
The Stability ◽  
The Relationship ◽  
Area Pellucida

Experiments have been carried out on explanted chick embryos to test certain widely accepted concepts about the role of Hensen's node in somite formation. The relationship between elongation of the area pellucida and regression of Hensen's node has also been investigated. We conclude from these experiments that: (a) The timing of somite formation is not controlled by the regression of Hensen's node, nor by the shearing of the mesoderm into right and left halves. (b) Somite size and shape are probably controlled by local conditions in the chick embryo. (c) Elongation and regression are two different events. (d) The position of the somites probably depends on mechanical tensions in the area pellucida. (e) The notochord is not required for the stability of somites in vivo.

Homogeneous Zinc(II) Catalysis in Accelerated Vulcanization I. Reaction-Stage Modeling and Cross-Link Formation

1998 ◽  
Vol 71 (4) ◽  
pp. 750-765 ◽  
Author(s):  
Peter J. Nieuwenhuizen ◽  
Sandjai Timal ◽  
Jeroen M. van Veen ◽  
Jaap G. Haasnoot ◽  
Jan Reedijk
Keyword(s):  
Detailed Knowledge ◽  
Cross Link ◽  
Model Compounds ◽  
Zinc Compounds ◽  
Reaction Stage ◽  
Novel Approach ◽  
Cross Links ◽  
Link Formation ◽  
Stage Modeling

Abstract This paper reports a novel approach for the study of the mechanism of accelerated vulcanization, namely, Reaction-Stage Modeling (RSM). By carefully studying the reactivity of relevant model compounds under selected conditions, detailed knowledge about a particular reaction stage of vulcanization can be obtained. Background, experimental details and synthesis of model compounds are described. An RSM study after cross-link formation in the thiuram- and dithiocarbamate type vulcanization has been performed, and the role of zinc compounds herein was investigated. In contrast to earlier studies, it has appeared that at 140 °C, cross-links form from cross-link precursors solely via disproportionation. Allylic substitution was not observed. Zinc compounds act as catalysts for disproportionation, but especially ZDMC can be regarded as an efficient, soluble molecular turntable for sulfur atoms.

scholarly journals Tropoelastin production and tropoelastin messenger RNA activity. Relationship to copper and elastin cross-linking in chick aorta

1986 ◽  
Vol 237 (1) ◽  
pp. 17-23 ◽  
Author(s):  
D Tinker ◽  
J Geller ◽  
N Romero ◽  
C E Cross ◽  
R B Rucker
Keyword(s):  
Messenger Rna ◽  
Copper Deficiency ◽  
Degradation Products ◽  
Lysyl Oxidase ◽  
Proteolytic Processing ◽  
Cross Linking ◽  
Cross Link ◽  
Dietary Copper ◽  
Lysine Residues ◽  
Link Formation

The elastin content of the chick thoracic aorta increases 2--3-fold during the first 3 weeks post-hatching. The deposition of elastin requires the covalent cross-linking of tropoelastin by means of lysine-derived cross-links. This process is sensitive to dietary copper intake, since copper serves as cofactor for lysyl oxidase, the enzyme that catalyses the oxidative deamination of the lysine residues involved in cross-link formation. Disruption of cross-linking alters tissue concentrations of both elastin and tropoelastin and results in a net decrease in aortic elastin content. Autoregulation of tropoelastin synthesis by changes in the pool sizes of elastin or tropoelastin has been suggested as a possible mechanism for the diminished aortic elastin content. Consequently, dietary copper deficiency was induced to study the effect of impaired elastin cross-link formation on tropoelastin synthesis. Elastin in aortae from copper-deficient chicks was only two-thirds to one-half the amount measured in copper-supplemented chicks, whereas copper-deficient concentrations of tropoelastin in aorta were at least 5-fold higher than normal. In spite of these changes, however, increased amounts of tropoelastin, copper deficiency and decreased amounts of elastin did not influence the amounts of functional elastin mRNA in aorta. Likewise, the production of tropoelastin in aorta explants was the same whether the explants were taken from copper-sufficient or -deficient birds. The lower accumulation of elastin in aorta from copper-deficient chicks appeared to be due to extracellular proteolysis, rather than to a decrease in the rate of synthesis. Electrophoresis of aorta extracts, followed by immunological detection of tropoelastin-derived products, indicated degradation products in aortae from copper-deficient birds. In extracts of aortae from copper-sufficient chicks, tropoelastin was not degraded and appeared to be incorporated into elastin without further proteolytic processing.

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