scholarly journals Thiocyanate and chloride as competing substrates for myeloperoxidase

1997 ◽  
Vol 327 (2) ◽  
pp. 487-492 ◽  
Author(s):  
J. Christine van DALEN ◽  
W. Michael WHITEHOUSE ◽  
C. Christine WINTERBOURN ◽  
J. Anthony KETTLE
Keyword(s):  
Kinetic Study ◽  
Acid Production ◽  
Plasma Concentrations ◽  
Host Defence ◽  
Oxidation Products ◽  
Substrate Preference ◽  
Hypohalous Acids ◽  
Relative Specificity ◽  
The Individual

The neutrophil enzyme myeloperoxidase uses H2O2 to oxidize chloride, bromide, iodide and thiocyanate to their respective hypohalous acids. Chloride is considered to be the physiological substrate. However, a detailed kinetic study of its substrate preference has not been undertaken. Our aim was to establish whether myeloperoxidase oxidizes thiocyanate in the presence of chloride at physiological concentrations of these substrates. We determined this by measuring the rate of H2O2 loss in reactions catalysed by the enzyme at various concentrations of each substrate. The relative specificity constants for chloride, bromide and thiocyanate were 1:60:730 respectively, indicating that thiocyanate is by far the most favoured substrate for myeloperoxidase. In the presence of 100 mM chloride, myeloperoxidase catalysed the production of hypothiocyanite at concentrations of thiocyanate as low as 25 μM. With 100 μM thiocyanate, about 50% of the H2O2 present was converted into hypothiocyanite, and the rate of hypohalous acid production equalled the sum of the individual rates obtained when each of these anions was present alone. The rate of H2O2 loss catalysed by myeloperoxidase in the presence of 100 mM chloride doubled when 100 μM thiocyanate was added, and was maximal with 1 mM thiocyanate. This indicates that at plasma concentrations of thiocyanate and chloride, myeloperoxidase is far from saturated. We conclude that thiocyanate is a major physiological substrate of myeloperoxidase, regardless of where the enzyme acts. As a consequence, more consideration should be given to the oxidation products of thiocyanate and to the role they play in host defence and inflammation.

Substrates and products of eosinophil peroxidase

2001 ◽  
Vol 358 (1) ◽  
pp. 233-239 ◽  
Author(s):  
Christine J. van DALEN ◽  
Anthony J. KETTLE
Keyword(s):  
Hypochlorous Acid ◽  
Plasma Concentrations ◽  
Oxidation Products ◽  
Inflammatory Conditions ◽  
Eosinophil Peroxidase ◽  
Hypohalous Acids ◽  
Hypobromous Acid ◽  
Michaelis Constants ◽  
The One ◽  
Compound Ii

Eosinophil peroxidase has been implicated in promoting oxidative tissue damage in a variety of inflammatory conditions, including asthma. It uses H2O2 to oxidize chloride, bromide and thiocyanate to their respective hypohalous acids. The aim of this study was to establish which oxidants eosinophil peroxidase produces under physiological conditions. By measuring rates of H2O2 utilization by the enzyme at neutral pH, we determined the catalytic rate constants for bromide and thiocyanate as 248 and 223s−1 and the Michaelis constants as 0.5 and 0.15mM respectively. On the basis of these values thiocyanate is preferred 2.8-fold over bromide as a substrate for eosinophil peroxidase. Eosinophil peroxidase catalysed substantive oxidation of chloride only below pH6.5. We found that when eosinophil peroxidase or myeloperoxidase oxidized thiocyanate, another product besides hypothiocyanite was formed; it also converted methionine into methionine sulphoxide. During the oxidation of thiocyanate, the peroxidases were present as their compound II forms. Compound II did not form when GSH was included to scavenge hypothiocyanite. We propose that the unidentified oxidant was derived from a radical species produced by the one-electron oxidation of hypothiocyanite. We conclude that at plasma concentrations of bromide (20–120μM) and thiocyanate (20–100μM), hypobromous acid and oxidation products of thiocyanate are produced by eosinophil peroxidase. Hypochlorous acid is likely to be produced only when substrates preferred over chloride are depleted. Thiocyanate should be considered to augment peroxidase-mediated toxicity because these enzymes can convert relatively benign hypothiocyanite into a stronger oxidant.

scholarly journals Stereo-Selective Pharmacokinetics of Ilimaquinone Epimers Extracted from a Marine Sponge in Rats

Marine Drugs ◽  
2019 ◽  
Vol 17 (3) ◽  
pp. 171 ◽  
Author(s):  
Heebin Son ◽  
Keumhan Noh ◽  
InWha Park ◽  
MinKyun Na ◽  
Sangtaek Oh ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Elimination Rate ◽  
Systemic Exposure ◽  
Rat Plasma ◽  
Absolute Bioavailability ◽  
Anti Cancer ◽  
The Stability ◽  
The Individual ◽  
Intravenous And Oral Administration

An ilimquinone (IQ) mixture isolated from Hippiospongia metachromia, consisting of IQ and epi-ilimaquinone (epi-IQ), exerts anti-HIV, anti-microbial, anti-inflammatory, and anti-cancer effects. An HPLC-MS/MS method was developed for simultaneous determination of the two epimers in rat plasma, separating them using a biphenyl column. Ascorbic acid is added during the sample preparation to ensure the stability of both isomers. The plasma concentrations of the isomers were monitored following intravenous and oral administration of the IQ mixture in rats as well as the individual epimers that were separately orally administered. Compare to IQ, epi-IQ was much more stable in rat plasma, likely due to its configurations of decalin. Both substances decayed in more than bi-exponential pattern, with an elimination rate constant of 1.2 h−1 for IQ and 1.7 h−1 for epi-IQ. The epi-IQ was distributed more widely than IQ by about two-fold. Consequently, the clearance of epi-IQ was greater than that of IQ by about three-fold. The oral absolute bioavailability for IQ was 38%, and, that for epi-IQ, was 13%. Although the systemic exposure of IQ was greater than that of epi-IQ by ~8.7-fold, the clearance of each isomer was similar when administered either orally or intravenously, when normalized for bioavailability. The stereo-specific behavior of the isomers appears to originate from differences in both their tissue distribution and gastrointestinal permeability.

scholarly journals Levers to Improve Antibiotic Treatment of Lambs via Drinking Water in Sheep Fattening Houses: The Example of the Sulfadimethoxine/Trimethoprim Combination

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 561
Author(s):  
Aude A. Ferran ◽  
Marlène Z. Lacroix ◽  
Alain Bousquet-Mélou ◽  
Ivain Duhil ◽  
Béatrice B. Roques
Keyword(s):  
Drinking Water ◽  
Oral Bioavailability ◽  
Half Life ◽  
Plasma Concentrations ◽  
Oral Route ◽  
Disease Spread ◽  
Bacterial Diseases ◽  
Terminal Half Life ◽  
High Interindividual Variability ◽  
The Individual

To limit the spread of bacterial diseases in sheep fattening houses, antibiotics are often administered collectively. Collective treatments can be delivered by drinking water but data on the drug’s solubility in water or on plasma exposure of the animals are lacking. We first assessed the solubility of products containing sulfadimethoxine (SDM), associated or not with trimethoprim (TMP), in different waters. We then compared in lambs the SDM and TMP pharmacokinetic profiles after individual intravenous (IV) and oral administrations of SDM-TMP in experimental settings (n = 8) and after a collective treatment by drinking water with SDM-TMP or SDM alone in a sheep fattening house (n = 100 for each treatment). The individual water consumption during the collective treatments was also monitored to characterize the ingestion variability. We showed that TMP had a short terminal half-life and very low oral bioavailability, demonstrating that it would be unable to potentiate SDM by oral route. Conversely, SDM had a long terminal half-life of 18 h and excellent oral bioavailability. However, delivery by drinking water resulted in a very high interindividual variability of SDM plasma concentrations, meaning that although disease spread could be controlled at the group level, some individuals would inevitably be under- or over-exposed to the antibiotic.

scholarly journals NMR and Computational Studies as Analytical and High-Resolution Structural Tool for Complex Hydroperoxides and Diastereomeric Endo-Hydroperoxides of Fatty Acids in Solution-Exemplified by Methyl Linolenate

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4902
Author(s):  
Raheel Ahmed ◽  
Panayiotis C. Varras ◽  
Michael G. Siskos ◽  
Hina Siddiqui ◽  
M. Iqbal Choudhary ◽  
...  
Keyword(s):  
1H Nmr ◽  
Methyl Linolenate ◽  
Density Functional ◽  
Chemical Shifts ◽  
Multiple Bond ◽  
Three Dimensional ◽  
Intramolecular Hydrogen Bonding ◽  
Correlation Spectroscopy ◽  
Oxidation Products ◽  
The Individual

A combination of selective 1D Total Correlation Spectroscopy (TOCSY) and 1H-13C Heteronuclear Multiple Bond Correlation (HMBC) NMR techniques has been employed for the identification of methyl linolenate primary oxidation products without the need for laborious isolation of the individual compounds. Complex hydroperoxides and diastereomeric endo-hydroperoxides were identified and quantified. Strongly deshielded C–O–O–H 1H-NMR resonances of diastereomeric endo-hydroperoxides in the region of 8.8 to 9.6 ppm were shown to be due to intramolecular hydrogen bonding interactions of the hydroperoxide proton with an oxygen atom of the five-member endo-peroxide ring. These strongly deshielded resonances were utilized as a new method to derive, for the first time, three-dimensional structures with an assignment of pairs of diastereomers in solution with the combined use of 1H-NMR chemical shifts, Density Functional Theory (DFT), and Our N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) calculations.

α-Tocopherol concentration and stereoisomer composition in plasma and milk from dairy cows fed natural or synthetic vitamin E around calving

2006 ◽  
Vol 73 (2) ◽  
pp. 227-234 ◽  
Author(s):  
Guillermo E Meglia ◽  
Søren K Jensen ◽  
Charlotte Lauridsen ◽  
Karin Persson Waller
Keyword(s):  
Vitamin E ◽  
Dairy Cows ◽  
Plasma Concentrations ◽  
Dietary Treatment ◽  
Tocopheryl Acetate ◽  
Tocopherol Concentration ◽  
Blood Concentrations ◽  
Oral Supplementation ◽  
Periparturient Period ◽  
The Individual

The aim of this study was to compare the effects of supplementing dairy cows with 1000 IU/day of all-rac-α-tocopheryl acetate (SynAc), RRR-α-tocopheryl acetate (NatAc), or RRR-α-tocopherol (NatAlc), from approximately 3 weeks before estimated calving until 2 weeks after calving, on the concentration of α-tocopherol and its stereoisomers (RRR-, RSS-, RRS-, RSR- and the four 2S-forms of α-tocopherol) in blood and milk. An unsupplemented group was included as control. Blood samples were collected at 3, 2 and 1 weeks before estimated calving, at calving, and 3, 7 and 14 days after calving, while milk samples were taken twice within 24 h after calving and at 7 and 14 days in milk. Overall, time and treatment had significant effects on plasma α-tocopherol with higher concentrations in NatAc than in the other groups. In addition, SynAc had higher concentrations than Control, and NatAlc tended to be higher than Control. The lowest plasma concentrations were observed at calving and 3 days after calving. Independent of treatment, the concentration was higher in colostrum than in milk day 7 and 14 after calving. Analyses of the stereoisomer distribution in plasma and milk showed that, irrespective of dietary treatment, RRR-α-tocopherol was the most predominant form, constituting more than 86%, whereas the remaining part of α-tocopherol was made up by the three synthetic 2R isomers, while the 2S isomers only contributed less than 1% of the total α-tocopherol. In control cows and cows supplemented with natural vitamin E, the proportion of RRR-α-tocopherol in plasma and milk constituted more than 98% of the total α-tocopherol. In conclusion, the results indicate that daily oral supplementation of dairy cows with RRR-α-tocopheryl acetate gives the highest blood concentrations of α-tocopherol in the periparturient period. Analyses of the distribution of the individual stereoisomers of α-tocopherol further indicate that the bioavailability of RRR-α-tocopherol relative to synthetic stereoisomers in cattle is considerably higher than officially accepted until now.

scholarly journals Metabolic consequences of methylenecyclopropylglycine poisoning in rats

1991 ◽  
Vol 274 (2) ◽  
pp. 395-400 ◽  
Author(s):  
K Melde ◽  
S Jackson ◽  
K Bartlett ◽  
H S A Sherratt ◽  
S Ghisla
Keyword(s):  
Amino Acids ◽  
Ketone Bodies ◽  
Blood Glucose Concentration ◽  
Plasma Concentrations ◽  
Liver Mitochondria ◽  
Branched Chain Amino Acids ◽  
Oxidation Products ◽  
Rat Liver Mitochondria ◽  
Toxic Metabolite ◽  
Branched Chain

We describe the effects of methylenecyclopropylglycine in fasted rats. A 75% decrease in the blood glucose concentration and an increase of lactate and pyruvate were observed 6 h after administration of 100 mg of this amino acid/kg. By contrast with the effects reported for hypoglycin [Williamson & Wilson (1965) Biochem. J. 94, 19c-21c], the plasma concentrations of ketone bodies decreased after administration of methylenecyclopropylglycine and the concentrations of branched-chain amino acids in the plasma were increased 6-fold. The oxidation of decanoylcarnitine or of palmitate was nearly completely inhibited in rat liver mitochondria from methylenecyclopropylglycine-poisoned rats. The activities of acetoacetyl-CoA and of 3-oxoacyl-CoA thiolase were decreased to 25% and less than 10% of the controls. There was a pronounced aciduria, due to the excretion of dicarboxylic acids and of oxidation products of branched-chain amino acids. The accumulation of the toxic metabolite methylenecyclopropylformyl-CoA in the mitochondrial matrix was detected after administration of methylenecyclopropylglycine. Similarly we confirmed experimentally that methylenecyclopropylacetyl-CoA accumulates in mitochondria incubated with methylenecyclopropylpyruvate.

A phase I dose escalation and pharmacokinetic study of BIBF 1120 in combination with paclitaxel and carboplatin in patients with advanced gynecological malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3561-3561 ◽  
Author(s):  
P. Harter ◽  
J. Huober ◽  
J. Pfisterer ◽  
P. Wimberger ◽  
S. Loibl ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Geometric Mean ◽  
Tumor Therapy ◽  
Plasma Concentrations ◽  
Hematological Toxicity ◽  
Gynecological Malignancies ◽  
Gynecologic Tumor ◽  
The Individual ◽  
Bibf 1120

3561 Background: BIBF 1120 is an oral triple angiokinase inhibitor targeting VEGFR, PDGFR, FGFR kinases which might be interesting targets for gynecologic tumor therapy. Therefore, we performed a phase I study to evaluate maximal tolerated dose (MTD), safety, and pharmacokinetics (PK) of twice daily BIBF 1120 in combination with carboplatin AUC 5 and paclitaxel 175 mg/m2 q21 (CP) in patients with advanced or recurrent gynecological malignancies. Methods: 6 courses of CP and escalating bid doses of BIBF 1120 (2x100 mg to 2x250 mg) on the days without i.v. chemotherapy were administered. A 3 + 3 dose escalation design was followed. An additional cohort of 6 pts was treated on the MTD level. Results: Twenty-three pts were enrolled and 21 pts were treated with at least one cycle of CP and BIBF 1120. At 2x250 mg of BIBF 1120, two pts developed reversible CTCAE °3 and °4 elevations of AST and ALT in the first treatment course. MTD was determined as 200 mg BIBF 1120 bid for the combination with CP. Within the other dose cohorts (2x100 mg, n= 3, 2x150 mg, n= 4, 2x200 mg, n= 13) no dose limiting toxicities were observed. There was no increase in hematological toxicity with the addition of BIBF 1120 compared to standard CP. Further non-hematological °3 toxicities were: diarrhea (n=4), ascites (n=1), dyspnoe (n=1), nausea (n=3).Thus far, the PK profiles of carboplatin, paclitaxel, and BIBF 1120 have been evaluated in seven pts (2x100 mg, n=3 and 2x150 mg, n=4). There was no significant change of the individual and geometric mean plasma concentrations of C and P before and after 3 weeks of continuous daily bid dosing with BIBF 1120. Conclusions: BIBF 1120 can be given safely at a dose of 200 mg bid together with standard doses of CP in pts with advanced gynecological malignancies. Preliminary PK analyses did not reveal any interaction of CP and BIBF 1120. [Table: see text]

Effects of hysterectomy and in-vivo treatment with uterine extracts on plasma concentrations of growth hormone, thyrotrophin and thyroid hormones in rats: a kinetic study

1984 ◽  
Vol 101 (3) ◽  
pp. 243-248 ◽  
Author(s):  
J. Bíró ◽  
P. Eneroth ◽  
E. M. Ritzén
Keyword(s):  
Growth Hormone ◽  
Thyroid Hormones ◽  
Kinetic Study ◽  
Plasma Concentrations ◽  
Adult Rats ◽  
In Vivo Treatment ◽  
Plasma Gh

ABSTRACT Plasma concentrations of GH, TSH, tri-iodothyronine (T3) and thyroxine (T4) were measured in adult rats 2 and 4 weeks after ovariectomy and ovariohysterectomy. Two weeks after ovariohysterectomy, the concentration of GH was significantly higher, but TSH and T3 concentrations were significantly lower than in rats which had been ovariectomized only. Hysterectomy had no effect on plasma GH and TSH concentrations if it was performed 2 weeks after ovariectomy. Plasma T3 had decreased by 2 weeks after ovariectomy but returned to pretreatment levels by 4 weeks. Recovery of the plasma T3 concentration was not observed if ovariectomy was followed by hysterectomy, since a further decrease of plasma T3 occurred. Plasma T4 was not significantly influenced either by ovariectomy or by ovariohysterectomy. Steroid-free uterine extracts given i.p. to ovariohysterectomized rats reduced plasma GH within 24 h of injection. Increases in plasma TSH, T3 and T4 were achieved in ovariohysterectomized rats with injections of uterine extracts (from intact, oestrogen-treated or castrated rats), but the increases were not consistent for the three hormones either as regards time after injection, nor for which particular extracts were effective. It was concluded that the uterus may contain factors which influence the GH storage and secretion and TSH-thyroid regulation in rats. J. Endocr. (1984) 101, 243–248

Kinetic study of succinic acid production by Actinobacillus succinogenes ZT-130

2008 ◽  
Vol 43 (10) ◽  
pp. 1047-1053 ◽  
Author(s):  
Rosa Isela Corona-González ◽  
Andre Bories ◽  
Víctor González-Álvarez ◽  
Carlos Pelayo-Ortiz
Keyword(s):  
Succinic Acid ◽  
Kinetic Study ◽  
Acid Production ◽  
Actinobacillus Succinogenes ◽  
Succinic Acid Production
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