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Biomedical subjects

A Kalir

Publications and source records attributed to A Kalir.

29 records · Page 2Linked to original sources
PubMed1976

Synthesis and properties of 2-S-(N,N-dialkylamino)ethyl)thio-1,3,2-dioxaphosphorinane 2-oxide and of the corresponding quaternary derivatives as potential nontoxic antiglaucoma agents.

A new series of cyclic organophosphorus esters, 2-S-[2'-N,N-dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide and their quaternary derivatives, was synthesized and studied as potential antiglaucoma agents. Thes compounds inhibit acetylcholinesterase (E.C.3.1.1.7)at a bimoecular rate constant (ki) in the range of 10(3)-10(4) M-1 min-1. Values of the affinity (K) and phosphorylation (k') rate constants for this enzyme indicate that k' is responsible for the relatively low values of ki as compared with similar data for the open-chain analogues, O,O-diethyl phosphorothiolates (10(6) M-1 min-1). The mammalian toxicity of the new compounds in terms of acute LD50 values in mice is 1-3 x 10(3) less than that of phospholine, an open-chain analogue. In an initial clinical trial, one member of the new series (alkyl = C2H5) caused a significant decrease of intraocular pressure in aphakic glaucoma, while phospholine proved to be ineffective.

Animals↗
PubMed1976

Effect of Salinity on Respiratory Pathways in Root Tips of Tamarix tetragyna.

Oxygen uptake in the presence of exogenous glucose was lower in Tamarix root tips grown in saline media than in those grown in Hoagland solution. This effect was not overcome by raising the external glucose concentration.Glucose uptake and CO(2) evolution were depressed in the presence of NaCl. This effect was observed also when roots were exposed to salinity only during growth but not during uptake. Increasing the external concentration of glucose from 0.01 to 1 mm induced only a 10-fold increase in glucose uptake and CO(2) evolution. However, (14)C evolved in CO(2) as percent of (14)C absorbed, remained constant at all salinity treatments, and was similar at both glucose concentrations.Salinity above 120 mm NaCl increased the percentage of absorbed glucose oxidized via the pentose phosphate pathway, but did not affect the glycolytic pathway. At the same time, salinity depressed the glucose-6-P dehydrogenase, pyruvate kinase, and oxidative phosphorylation. These effects become most evident at a salinity level of about - 10 atm (240 mm), a concentration which is rarely exceeded in the root zone of the natural habitat of the plants.We concluded that Tamarix is reasonably well adapted to the conditions of its habitat, and that salinity affects its root metabolism differently than it does that of pea roots.

Journal Article↗
PubMed1975

Malic dehydrogenase from tamarix roots: effects of sodium chloride in vivo and in vitro.

Soluble and mitochondrial malic dehydrogenases (MDH) were isolated from root tips of the halophyte Tamarix tetragyna L. grown in the presence and absence of NaCl. The activity of the enzymes isolated from root tips grown in the presence of NaCl was lower than that of the enzymes isolated from roots grown in absence of NaCl. The mitochondrial MDH was much more sensitive to salinity than the soluble MDH. The soluble enzyme from roots grown in NaCl had a higher Km for malate and lower Km for NAD than enzyme from the control roots. Addition of NaCl in vitro at 72 mM significantly stimulated the reductive activity of soluble MDH, while higher NaCl concentrations (240 mM and above) depressed enzyme activity. The inhibition of enzyme activity by various salts was found to be in the order MgCl(2) > NaCl = KCl > Na(2)SO(4). Mannitol at equiosmotic concentrations had no effect. Substrate inhibition, typical for oxaloacetate oxidation, was not observed at high NaCl concentrations in vitro and high substrate concentrations neutralized the inhibitory effect of NaCl. Increased coenzyme concentrations had no effect. In vitro NaCl increased the Km for malate and oxaloacetate already at relatively low concentrations. At the same time NaCl decreased the Km for NAD and NADH. The inhibitory effect of NaCl on enzyme activity seems not to be due to the effect on the Km alone. Soluble and mitochondrial MDH had different responses to pH changes, mitochondrial MDH being more sensitive. Mitochondrial MDH released from the particles had a similar response to that of the entire particles. Changes of pH modified the effect of NaCl on enzyme activity. It was postulated that NaCl apparently induces conformational changes in the enzyme.

Journal Article↗
PubMedDate not supplied

Phencyclidine iminium ion. NADPH-dependent metabolism, covalent binding to macromolecules, and inactivation of cytochrome(s) P-450.

The phencyclidine iminium ion (PCP-Im+), a potentially reactive 2,3,4,5-tetrahydropyridinium species, is formed by the cytochrome(s) P-450-catalyzed alpha-carbon oxidation of phencyclidine (PCP), a commonly abused psychotomimetic agent. Incubation of PCP-Im+ with liver microsomes obtained from phenobarbital-induced rabbits resulted in over 50% loss of microsomal N-demethylase activity and 30% reduction in cytochrome(s) P-450 content. These effects were concentration-dependent, irreversible, and exhibited pseudo-first order kinetics, characteristics of a mechanism-based enzyme inactivation process. Incubation of 3H-PCP-Im+ with liver microsomes resulted in covalent binding of radioactive material to macromolecules by a process that also was NADPH-dependent. PCP-Im+ was metabolized by liver microsomes in the presence of NADPH and this metabolism was inhibited by SKF 525A and carbon monoxide. HPLC analysis has led to the preliminary characterization of an oxidized metabolite of PCP-Im+ which also is formed from PCP. These results support the proposal that this tetrahydropyridinium metabolite of PCP is biotransformed in a cytochrome(s) P-450-catalyzed reaction to form reactive species capable of covalent interactions with biomacromolecules.

Animals↗
PubMedDate not supplied

Metabolism of phencyclidine. The role of iminium ion formation in covalent binding to rabbit microsomal protein.

Incubation of phencyclidine (PCP) with rabbit liver microsomes and Na14CN resulted in the metabolically dependent formation of a 14C-labeled cyano adduct of the drug. After isolation by HPLC, this compound was identified as the alpha-aminonitrile [1-(1-phenylcyclohexyl)-2-cyanopiperidine] derivative of PCP by use of chemical-ionization and gas-chromatographic coupled electron-impact mass spectrometry. Synthetic alpha-aminonitrile exhibited identical chemical properties and comigrated in HPLC and GLC with the metabolism derived cyano adduct. Molecular identification of the adduct formed by cyanide trapping provided evidence for the formation of an iminium ion during PCP metabolism. Quantitative estimation by HPLC demonstrated that the alpha-aminonitrile accounted for over 50% of the PCP metabolized in 30 min by hepatic microsomes in vitro. Metabolism-dependent covalent binding of [3H]PCP to rabbit liver microsomal proteins was inhibited by cyanide ion in a concentration-dependent manner with an IC50 value of 57 microM. The concentrations of cyanide ion used in these experiments did not significantly inhibit the metabolism of PCP. These results support our suggestions that iminium ion formation may represent an important intermediary step in the metabolism of PCP and that such a reactive electrophilic species may be capable of covalent interactions with nucleophilic groupings on microsomal macromolecules.

Animals↗