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PubMed2006

Thermodynamics of pyridine coordination in 1,4-phenylene bridged bimetallic (Pd, Pt) complexes containing two N,C,N' motifs, 1,4-M2-[C6(CH2NR2)4-2,3,5,6].

The thermodynamics of pyridine coordination in 1,4-phenylene-bridged binuclear palladium and platinum organometallic complexes [1,4-(MOTf)2-&{C6(CH2NR2)4-2,3,5,6}] (11, M =Pd, Pt; R =CH3, C2H5, R2 = -(CH2)5-) are measured by 1H NMR in DMSO-d6. The coordination of substituted pyridines by bimetallic complexes 11 or 12 in DMSO is found to proceed via two effectively independent metalligand binding events, and the association constants for pyridine coordination and rate constants for pyridine exchange are nearly identical to those measured previously on monometallic analogs. A linear free energy relationship between the association constant for pyridine coordination and the inductive Hammett constant of the pyridine substituent is observed, and the sensitivity (rho = -1.7 to -2.1) in DMSO depends only slightly on metal (Pd vs Pt) and spectator ligand (pincer dialkylamine vs triarylphosphine). The association constant for a particular pyridine ligand, however, varies by roughly 3 orders of magnitude across the series of metal complexes. The effective independence of the two coordination sites and the range of available thermodynamic and kinetic behaviors of the coordination guide the use of these versatile building blocks in metallosupramolecular applications.

Organometallic Compounds↗

PubMed2001

Two new elastin cross-links having pyridine skeleton. Implication of ammonia in elastin cross-linking in vivo.

Isolation and structure analysis of two amino acids from bovine ligamentum nuchae elastin hydrolysates revealed the presence of pyridine cross-links in elastin. The structures of these amino acids were determined to have 3,4,5- and 2,3,5-trisubstituted pyridine skeletons both with three carboxylic acids and a mass of 396 (C(18)H(28)N(4)0(6)) identified as 4-(4-amino-4-carboxybutyl)-3,5-di-(3-amino-3-carboxypropyl)-pyridine and 2-(4-amino-4-carboxybutyl)-3,5-di-(3-amino-3-carboxypropyl)-pyridine. We have named these pyridine cross-links desmopyridine (DESP) and isodesmopyridine (IDP), respectively. Structure analysis of these pyridine cross-links implied that the formation of these cross-links involved the condensation reaction between ammonia and allysine. The elastin incubated with ammonium chloride showed that DESP and IDP levels increased as the allysine content decreased. DESP and IDP were measured by high pressure liquid chromatography (HPLC) with UV detection and were found in a variety of bovine tissues. The DESP/desmosine (DES) and IDP/isodesmosine (IDE) ratios in aorta elastin were higher than in other tissues. DESP and IDP contents in human aorta elastin were found to be gradually increased with age. The concentration of IDP was significantly elevated in aorta elastin of rat with chronic liver cirrhosis induced by carbon tetrachloride (mean +/- S.D.; 11.1 +/- 0.9 nmol/mg elastin) when compared with normal rats (5.9 +/- 1.5 nmol/mg elastin). Although DESP and IDP are present at only trace concentrations in the tissue elastin, these pyridine cross-links may be useful biomarkers for the aortic elastin damaged by ammonia.

2-Aminoadipic Acid↗

PubMed2002

Identification of pyridine compounds in cigarette smoke solution that inhibit growth of the chick chorioallantoic membrane.

Based on prior work, we hypothesized that cigarette smoke contains chemicals that can inhibit growth of the chick chorioallantoic membrane (CAM). In this study, gas chromatography and mass spectrometry were used to identify 12 pyridine derivatives in the inhibitory fractions of smoke eluted from solid phase extraction cartridges. These pyridine derivatives were further studied individually in dose response experiments to determine their effects on CAM growth. A correlation was observed between the functional group substitutions on pyridine and the relative toxicity of each pyridine derivative. In the CAM growth assay, pyridine derivatives with single methyl or single ethyl substitutions had lowest observed adverse effect levels (LOAELs) of 5 x 10(-9) and 5 x 10(-12) M, respectively. Other pyridine derivatives and pyridine itself had LOAELs in the micromolar range. One of the most inhibitory derivatives, 3-ethylpyridine, was studied further and inhibited cell proliferation, as measured by BrdU incorporation. Since 3-ethylpyridine inhibited growth at picomolar doses and is added to consumer products including cosmetics, food, drinks, and tobacco, it will be important to perform further toxicological testing to determine its effect on human health.

Animals↗

PubMed2002

Synthesis and pharmacological activities of 2-(3'-substituted-2'-hydroxypropylamino)pyridines.

In the present study, a series of 2-(3'-substituted-2'-hydroxypropylamino)pyridines were synthesized and characterized by IR, 1H-NMR and elemental analysis. The compounds were investigated for anticonvulsant (150, 300 mg/kg) and cardiac activity. 2-(3'-Diethylamino-2'-hydroxypropylamino)pyridine 3 was found to exhibit the highest anticonvulsant activity. 2-(3'-Dimethylamino-2'-hydroxypropylamino)pyridine 2 and 2-[3'-(4''-nitrophenylamino)-2'-hydroxypropylamino]pyridine 6 were found to exhibit negative ionotropic activity. 2-(3'-Dimethylamino-2'-hydroxypropylamino)pyridine 2, 2-[3'-(4''-nitrophenylamino)-2'-hydroxypropylamino]pyridine 6 and 2-(3'-piperidino-2'-hydroxypropylamino)pyridine 8 were found to antagonize exhibit beta-adrenergic activity.

Animals↗

PubMed1998

A novel cell-free system for peptide synthesis driven by pyridine.

Previously we demonstrated that ribosomes can synthesize polypeptides in the presence of high concentrations (40-60%) of pyridine without any protein factors. Here we analyze additional ribosomal parameters in 60% pyridine using Escherichia coli ribosomes. Ribosomal subunits once exposed to pyridine failed to re-associate to 70S ribosomes in aqueous buffer systems even in the presence of 20 mM Mg2+, whereas they formed 70S complexes in the presence of 60% pyridine. Two-dimensional gel electrophoresis of ribosomal proteins revealed that some proteins located at the protuberances of the large subunit, e. g. L7/L12 and L11 forming the elongation factor-binding domain, were released in the pyridine system. The aminoglycoside neomycin, a strong inhibitor of the ribosomal (factor-independent) translocation reaction, completely blocked poly(Phe) synthesis and translocation activities in the pyridine system, whereas these activities were not affected at all by gypsophilin, a ribotoxin that inhibits factor-dependent translocation. Another inhibitor of the ribosomal translocation, thiostrepton, had no effect concerning the two activities, which is consistent with the fact that this antibiotic requires L11 for its binding to the ribosome. These results suggest that the ribosomes can perform a translocation reaction in the pyridine system, but in a factor-independent (spontaneous) manner.

Cell-Free System↗

PubMed1979

Some factors involved in the N-oxidation of 3-substituted pyridines by microsomal preparations in vitro.

1. Pyridine-N-oxides have been identified as metabolites in vitro of several 3-substituted pyridines. 2. Factors affecting the metabolism of these pyridines in vitro have been studied, and conditions which give the most metabolism have been established. 3. 'Pyridine-N-oxidase' activity resides mainly in the hepatic and pulmonary microsomal fractions. 4. A species difference was evident with 'pyridine-N-oxidase' activity decreasing in the order hamster, rabbit, mouse, guinea-pig and rat. 5. A sex difference in 'pyridine-N-oxidase' activity was also established in rats and mice. 6. The appropriate kinetic factors, Km and Vmax for the N-oxidation of pyridine, 3-methylpyridine and 3-chloropyridine are reported.

Animals↗

PubMedDate not supplied

Synthesis and antiproliferative activity in vitro of new 3-substituted aminoisoxazolo[5,4-b]pyridines.

The synthesis of 3-aminoisoxazolo[5,4-b]pyridine [III] and of several new 3-substituted aminoisoxazolo[5,4-b]pyridines is described. 3-Aminoisoxazlo[5,4-b]pyridine [III] was subjected to reactions with the acid halides and substituted aromatic aldehydes, leading to the production of the corresponding amides IV-VII, IX, XI-XVI and new tricyclic pyridoisoxazolopyrimidine VIII and Schiff bases XX-XXIV. 4-Chlorobutyroamide IX cyclized into 3-(pyrrolidinon-1-yl)isoxazolo[5,4-b]pyridine [X]. 3-Chloroacetylaminoisoxaxolo[5,4-b]pyridine [V] in reaction with secondary amines gave 3-aminoacetylaminoisoxazolo[5,4-b]pyridines XVII-XIX. The structures of the products II-XXIV were established on the basis of elemental analysis and spectral data IR, 1H NMR and MS. Selected compounds were tested for their antiproliferative activity in vitro. Two of them: 3-chloroacetyl-[V] and 3-2-bromo-propionylaminoisoxazolo[5,4-b]pyridine [VI] revealed cytotoxic activity against the cells of 8 various human or mouse tumor cell lines applied. Their ID50 (inhibitory dose 50%) values are in the range of the international activity criterion for synthetic agents (4 microg/ml).

Antineoplastic Agents↗

PubMed1990

Two pyridine analogues with more effective ability to reverse multidrug resistance and with lower calcium channel blocking activity than their dihydropyridine counterparts.

Four pyridine analogues and their dihydropyridine counterparts were examined for their ability to reverse drug resistance in a multidrug-resistant human carcinoma cell line, KB-C2. Two pyridine analogues were more able to reverse drug resistance than their dihydropyridine counterparts. The other two pyridine analogues had an effect on drug resistance similar to their dihydropyridine counterparts. The calcium channel-blocking activity of all the pyridine analogues was considerably lower than that of the dihydropyridine analogues. Of the pyridine analogues, 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl 5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4 -(3- nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) was the most effective in reversing multidrug resistance. PAK-104P (1 and 5 microM) completely reversed the drug resistance in KB-8-5 and KB-C2 cells, respectively. The reversing effect of PAK-104P was greater than that of other multidrug resistance-reversing agents, cepharanthine, verapamil, nimodipine, and nicardipine. PAK-104P at 1 microM increased about 10-fold the accumulation of vinblastine in KB-C2 cells, whereas verapamil at the same concentration increased the accumulation about 2-fold. The inhibition of [3H]azidopine photolabeling of P-glycoprotein by the pyridine and dihydropyridine analogues except 2-[methyl(phenyl-methyl)amino]ethyl 4-(2-chlorophenyl)-5-(4-methyl-1,3,2-dioxaphosphorinan-2-yl)-1,4-d ihydro-2,6- dimethyl-3-pyridinecarboxylate P-oxide correlated with the reversing of drug resistance by the analogues. Some newly synthesized pyridine analogues seemed to have lower calcium channel-blocking activity and more potent resistance-reversing ability than verapamil and other calcium channel blockers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1984

Effects of pyridine and some of its derivatives on prostaglandin synthesis.

Effects of pyridine and some of its derivatives namely, nicotinic acid, nicotinyl alcohol, pyridinol carbamate, pyridoxine hydrochloride and pyridostigmine bromide were investigated on the release of a prostaglandin E2-like substance (PGE2-LS) from the isolated perfused rat heart. Furthermore, the effect of neostigmine bromide was also studied as a non-pyridine control compound. At 2 X 10(-5) M concentration, only pyridoxine hydrochloride stimulated the release of PGE2-LS significantly. At 2 X 10(-4) M concentration, pyridine, nicotinic acid and pyridinol carbamate were also found to be active in addition to pyridoxine hydrochloride. At 1 X 10(-3) M concentration, pyridine and all of its derivatives studied increased the release of PGE2-LS significantly. However, neostigmine bromide (1 X 10(-3) M) failed to exert any effect. Indomethacin, a prostaglandin synthetase inhibitor, reduced both the basal release (28%) and the release stimulated by pyridine and its derivatives at 1 X 10(-3) M concentration (more than 50%). These findings suggest that the active substance released is a prostaglandin. It is concluded that the PGE2-LS releasing effect of pyridine and its derivatives from isolated rat heart may be due to the action of the pyridine moiety of the molecules of the compounds studied.

Animals↗

PubMed1998

Influence of pyridine and urea on the rat brain ATPase activity.

The neurotoxicity of pyridine and urea was investigated in respect to their ability to alter the activity of synaptosomal membrane Na+/K(+)-ATPase and Mg(2+)-ATPase. In vitro treatment with pyridine and urea stimulated Na+/K(+)-ATPase activity in a dose-dependent manner up to 40% and 60%, respectively. Mg(2+)-ATPase activity increased up to 40% after pyridine treatment, while urea had no effect at all. The neuroactive potencies of pyridine and urea were evaluated by estimating parameters Km and delta Vmax for enzyme stimulation, as well as Hill coefficient to estimate the levels of cooperativity for pyridine and urea binding. The results suggest that pyridine stimulates both enzymes, probably by interacting with some neuronal membrane components, and altering the lipid micro-environment of the ATPases. In contrast, urea stimulates the Na+/K(+)-ATPase only, assumingly by acting on it directly or via some other regulatory mechanism. Stimulation of Na+/K(+)-ATPase and Mg(2+)-ATPase by the substances tested and subsequent alteration of neuronal cell functioning could contribute to the CNS dysfunction upon chronic exposure to pyridine and urea.

Animals↗

PubMed2005

Theoretical analysis of pyridine protonation in water clusters of increasing size.

The protonation of pyridine in water clusters as a function of the number of water molecules was theoretically analyzed as a prototypical case for the protonation of organic bases. We determined the variation of structural, bonding, and energetic properties on protonation, as well as the stabilization of the ionic species formed. Thus, we used supermolecular models in which pyridine interacts with clusters of up to five water molecules. For each complex, we determined the most stable unprotonated and protonated structures from a simulated annealing at the semi ab initio level. The structures were optimized at the B3LYP/cc-pVDZ level. We found that the hydroxyl group formed on protonation of pyridine abstracts a proton from the ortho-carbon atom of the pyridine ring. The "atoms in molecules" theory showed that this C-H group loses its covalent character. However, starting with clusters of four water molecules, the C-H bond recovers its covalent nature. This effect is associated with the presence of more than one ring between the water molecules and pyridine. These rings stabilize, by delocalization, the negative charge on the hydroxyl oxygen atom. Considering the protonation energy, we find that the protonated forms are increasingly stabilized with increasing size of the water cluster. When zero-point energy is included, the variation follows closely an exponential decrease with increasing number of water molecules. Analysis of the vibrational modes for the strongest bands in the IR spectra of the complexes suggests that the protonation of pyridine occurs by concerted proton transfers among the different water rings in the structure. Symmetric water stretching was found to be responsible for hydrogen transfer from the water molecule to the pyridine nitrogen atom.

Journal Article↗

PubMed2003

Inhibition of cholinesterases with cationic phosphonyl oximes highlights distinctive properties of the charged pyridine groups of quaternary oxime reactivators.

Oxime-induced reactivation of phosphonylated cholinesterases (ChEs) produces charged phosphonyl pyridine oxime intermediates (POXs) that are most potent organophosphate (OP) inhibitors of ChEs. To understand the role of cationic pyridine oxime leaving groups in the enhanced anti-ChE activity of POXs, the bimolecular rate constants for the inhibition (k(i)) of acetylcholinesterases (AChE) and butyrylcholinesterases (BChE), and the rate of decomposition (k(d)) of authentic O-alkyl methylphosphonyl pyridine oximes (AlkMeP-POXs) and N,N-dimethylamidophosphoryl pyridine oximes (EDMP-POXs), were studied. Stability ranking order in aqueous solutions correlated well with the electronic features and optimized geometries that were obtained by ab initio calculations at 6-31G(**) basis set level. AlkMeP-POXs of the 2-pyridine oxime series were found to be 4- to 8-fold more stable (t(1/2)=0.7 to 1.5 min) than the homologous O,O-diethylphosphoryl (DEP) oxime. Results suggest that re-inhibition of enzyme activity by POX is less likely during the reactivation of DEP-ChEs (obtained by use of DEP-containing pesticides) by certain oximes, compared to nerve agent-inhibited ChEs. The greatest inhibition was observed for the O-cyclohexyl methylphosphonyl-2PAM derivative (4.0 x 10(9)M(-1)min(-1); mouse AChE) and is 10-fold higher than the k(i) of cyclosarin. Increasing the size of the O-alkyl substituent of AlkMeP-POXs had only a small to moderate effect on the k(i) of ChEs, signifying a major role for the cationic pyridine oxime leaving group in the inhibition reaction. The shape of plots of logk(i) vs. pK(a) of the leaving groups for AlkMeP-PAMs and DEP-PAMs, could be used as a diagnostic tool to highlight and rationalize the unique properties of the cationic moiety of pyridine oxime reactivators.

Animals↗

PubMed2003

Reactions of the dirhenium(II) complex Re2Cl4(mu-dppm)2 with pyridinecarboxylic acids. Examples of bidentate O,O versus N,O coordination and tridentate O,N,O coordination and structural isomers that contain the pyridine-2,6-dicarboxylate ligand.

Pyridine-2-carboxylic acid, pyridine-2,3-dicarboxylic acid, and pyridine-2,4-dicarboxylic acid or their [(Ph(3)P)(2)N](+) salts react with the triply bonded dirhenium(II) complex Re(2)Cl(4)(mu-dppm)(2) (dppm = Ph(2)PCH(2)PPh(2)) in refluxing ethanol to afford unsymmetrical substitution products of the type Re(2)(eta(2)-N,O)Cl(3)(mu-dppm)(2), where N,O represents a chelating pyridine-2-carboxylate ligand (N,O = O(2)C-2-C(5)H(4)N (1), O(2)C-2-C(5)H(3)N(-3-CO(2)Et) (3), or O(2)C-2-C(5)H(3)N(-4-CO(2)H) (4)). The carboxylate groups in the 3- and 4- positions are not bound to the metal centers; in the case of 3 this group undergoes esterification in the refluxing ethanol solvent. Structure determinations have shown that 1, 3, and 4 possess similar structures in which there is an axial Re-O (carboxylate) bond (collinear with the Re(triple bond)Re bond) and the mu-dppm ligands are bound in a trans,cis fashion to the two Re atoms which have the ligand atom arrangement [P(2)NOClReReCl(2)P(2)]. The tridentate dianionic pyridine-2,6-dicarboxylate ligand (dipic) reacts with Re(2)Cl(4)(mu-dppm)(2) in ethanol at room temperature to give a compound Re(2)(dipic)Cl(2)(mu-dppm)(2) (6) in which the dipic ligand is bound in a symmetrical eta(3)-(O,N,O) fashion to one Re atom, with the N atom in an axial position (collinear with the Re(triple bond)Re bond) and with preservation of the same trans,trans coordination of the mu-dppm ligands that is present in Re(2)Cl(4)(mu-dppm)(2). Under reflux conditions, this kinetic product isomerizes to the thermodynamically favored isomer 5 with an unsymmetrical structure in which the dipic ligand chelates to one Re atom (as in 1, 3, and 4) and uses its other carboxylate group to bridge to the second Re atom. The isomerization of 6 to 5, which also results in a change in the coordination of the pair of mu-dppm ligand to trans,cis, is believed to occur by a partial "merry-go-round" process, a mechanism that probably explains the structures of the thermodynamic products 1, 3, and 4. The reaction of Re(2)Cl(4)(mu-dppm)(2) with pyridine-3-carboxylate gives the trans isomer of Re(2)(mu:eta(2)-O(2)C-3-C(5)H(4)N)(2)Cl(2)(mu-dppm)(2) (2) in which a pair of carboxylate bridges are present and the pyridine N atom is not coordinated. Single-crystal X-ray structural details are reported for 1-6.

Journal Article↗

PubMed2002

Recurrence of carboxylic acid-pyridine supramolecular synthon in the crystal structures of some pyrazinecarboxylic acids.

X-ray crystal structures of pyrazinic acid 1 and isomeric methylpyrazine carboxylic acids 2-4 are analyzed to examine the occurrence of carboxylic acid-pyridine supramolecular synthon V in these heterocyclic acids. Synthon V, assembled by (carboxyl)O-H...N(pyridine) and (pyridine)C-H...O(carbonyl) hydrogen bonds, controls self-assembly in the crystal structures of pyridine and pyrazine monocarboxylic acids. The recurrence of acid-pyridine heterodimer V compared to the more common acid-acid homodimer I in the crystal structures of pyridine and pyrazine monocarboxylic acids is explained by energy computations in the RHF 6-31G* basis set. Both the O-H.N and the C-H...O hydrogen bonds in synthon V result from activated acidic donor and basic acceptor atoms in 1-4. Pyrazine 2,3- and 2,5-dicarboxylic acids 10 and 11 crystallize as dihydrates with a (carboxyl)O-H...O(water) hydrogen bond in synthon VII, a recurring pattern in the diacid structures. In summary, the carboxylic acid group forms an O-H...N hydrogen bond in pyrazine monocarboxylic acids and an O-H...O hydrogen bond in pyrazine dicarboxylic acids. This structural analysis correlates molecular features with supramolecular synthons in pyridine and pyrazine carboxylic acids for future crystal engineering strategies.

Journal Article↗

PubMed2005

Theoretical study of pyridine and 4,4'-bipyridine adsorption on the lewis acid sites of alumina surfaces based on ab initio and density functional cluster calculations.

The interactions of pyridine and 4,4'-bipyridine with the Lewis acid sites of alumina surfaces are investigated using ab initio and density functional calculations. Four cluster models of different sizes and shapes are chosen to represent the Lewis acid sites: three hydrogenated clusters Al(OH)(3), Al(4)O(9)H(6), and Al(10)O(21)H(12) and one non-hydrogenated cluster Al(4)O(6). The Hartree-Fock (HF) and B3LYP approaches with two basis sets 6-31G and 6-31+G are used to calculate the geometries, the electronic structures, the vibrational frequencies, and the adsorption energies of the complexes formed upon interaction of pyridine or 4,4'-bipyridine ligands on the cluster surfaces. Electronic structures are determined by the electrostatic potential (ESP) analysis of charges. Adsorption energies are calculated with corrections made for zero-point energies (ZPE) and basis set superposition error (BSSE). The ESP analysis of atomic charges reveals that the charge-transfer effects are more important in Lewis complexes formed with Al(4)O(6) cluster than in those formed with hydrogenated clusters Al(OH)(3), Al(4)O(9)H(6), and Al(10)O(21)H(12). The significantly larger charge transferred from pyridine or 4,4'-bipyridine ligand to Al(4)O(6) cluster should increase the adsorption energy of these complexes. Consequently, at all levels of calculation, the adsorption energies of pyridine and 4,4'-bipyridine complexed to Al(4)O(6) cluster ( approximately 46 kcal/mol), which compare very well to experiment, are strongly larger than those obtained for both pyridine and 4,4'-bipyridine ligands complexed to Al(OH)(3) (32 kcal/mol), Al(4)O(9)H(6) (24 kcal/mol) and Al(10)O(21)H(12) (25 kcal/mol) clusters. The corrected adsorption energy is found to be insensitive to basis set and electron correlation effects. It essentially depends on the ionic character of the cluster model rather than on its size. For 4,4'-bipyridine complexes, similar results to those obtained for pyridine are found, and the geometry and the amount of charge of the unbound pyridyl ring are unchanged upon complexation. The calculated vibrational frequencies and frequency shifts are little sensitive to the size and shape of the cluster model. The two ring stretching modes 8a and 19b of pyridine and 4,4'-bipyridine observed in the 1400-1600 cm(-1) region are the most affected modes upon adsorption, in good agreement with the available infrared and Raman data.

Journal Article↗

PubMed1993

Hydroperoxide-induced oxidative stress alters pyridine nucleotide metabolism in neonatal heart muscle cells.

An oxidant burden established by hydrogen peroxide (H2O2) overload may elicit postischemic myocardial damage. We assess herein the influence of H2O2-induced oxidative stress on heart muscle pyridine nucleotide metabolism. Exposure of neonatal rat cardiomyocytes to 50 microM-1.0 mM H2O2 bolus rapidly shifted their pyridine-nucleotide redox balance toward oxidation. At least 30% of the observed NADPH oxidation was independent of glutathione cycle activity and appeared chemical in nature with H2O2 itself, and not a radical metabolite, acting as oxidant. Cell exposure to H2O2 also depleted cardiomyocyte pyridine nucleotides as a consequence of enhanced utilization. The oxidative stress activated one major route of pyridine nucleotide catabolism (i.e., protein ADP-ribosylation) without acute inhibitory effect upon the other (cleavage by NAD glycohydrolase). The limited NAD sparing by metal chelators and inhibitors of ADP-ribosylation reflected pyridine nucleotide utilization for repair of single-strand DNA breaks caused by hydroxyl-like radicals formed intracellularly through iron-dependent H2O2 reduction. Cardiomyocyte NAD depletion during H2O2-induced oxidative stress was independent of cell integrity and lipid peroxidation. The NAD lost after a discrete H2O2 "pulse" was only partly replenished over a 24-h postinjury period. These data demonstrate that cardiomyocyte pyridine nucleotide metabolism is a nonperoxidative injury target that is chronically affected by H2O2 overload. Derangement of myocardial pyridine nucleotide pools due to oxidative stress may contribute to ischemic heart injury in vivo by interfering with cardiac hydrogen metabolism and redox balance.

Animals↗

PubMed1980

The metabolic N-oxidation of 3-substituted pyridines in various animal species in vivo.

The intraperitoneal administration of pyridine, 3-methylpyridine and 3-chloropyridine to mice, hamsters, rats, guinea-pigs, rabbits and ferrets, resulted in the urinary excretion of their N-oxides. Pyridine-N-oxide was found to be a quantitatively important metabolite of pyridine in all the species studied; the percentage of the dose excreted in the urine as pyridine-N-oxide ranged from 10% in rats to about 40% in mice and guinea-pigs. 3-Chloropyridine-N-oxide and 3-methylpyridine-N-oxide accounted for less than 7% of the administered dose of the parent base. The urinary excretion of pyridine-N-oxide was considerably greater in mice pretreated with phenobarbitone, compared to control mice, whereas 3-methylchloranthrene pretreatment had no appreciable effect on the excretion of pyridine-N-oxide.

Animals↗

PubMed2000

Induction of N-nitrosodimethylamine metabolism in liver and lung by in vivo pyridine treatments of rabbits.

N-Nitrosodimethylamine is a procarcinogen that is activated by cytochrome P450 dependent N-nitrosodimethylamine N-demethylase to labile alpha-carbon hydroxylated products further resulting in active methylating agents. In vivo intraperitoneal administration of pyridine to rabbits significantly increased N-nitrosodimethylamine N-demethylase activity by 6.9- and 5.2-fold in liver and lung microsomes, respectively. Although, p-nitrophenol hydroxylase and aniline 4-hydroxylase activities were markedly enhanced by pyridine treatment in liver about 4.4- and 5.8-fold, respectively, no change was observed in the activities of these enzymes in lung microsomes. Pyridine treatment also elevated P450 contents of liver and lung by 2.04- and 1.4-fold, respectively. SDS-PAGE of pyridine-induced liver microsomes revealed a protein band of enhanced intensity having Mr of 51,000 migrating in the region of cytochrome P4502E1. The results obtained in this study demonstrated for the first time, a significant 5.2-fold induction of NDMA N-demethylase activity in the rabbit lung over the controls. Pyridine is readily absorbed by inhalation and is a constituent of tobacco and tobacco smoke. Thus induction of NDMA N-demethylase suggests that in the lung, as in the liver, pyridine may stimulate the metabolic activation of this nitrosamine significantly.

Aniline Hydroxylase↗