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PubMed1997

Physicians prefer goal-oriented note format more than three to one over other outcome-focused documentation.

To assess preference for outcome-focused nutrition notes, two note formats were selected from the literature and tested against a modified, goal-oriented format. Focus charting and intervention, evaluation, and revision (IER) formats were compared with a charting-by-exception style that was modified to include goals and reassessment of risk. Notes were handwritten in each format and contained the same information. Physicians were asked to choose their preference and explain why that format was selected. Initially, focus charting was tested against the goal-oriented format. The more popular of the two was then tested against the IER format. Nineteen physicians were surveyed by a registered dietitian for each comparison. Physicians preferred the goal-oriented format over focus charting and IER formats 9:1 and 3:1, respectively. In the first survey, physicians preferred the goal-oriented format because the plan was clearly stated, thereby rendering the note easier to understand. The goal-oriented format was preferred in the second survey because the note was considered to be concise and easy to read and contained expected outcomes. Physicians want short communication that includes easily identifiable goals and plans. We recommend that experienced dietitians use the goal-oriented format developed for this study, and preferred by physicians, for follow-up nutrition notes.

Attitude of Health Personnel↗
PubMed1999

Comparison of glyceryl trinitrate-induced with pentaerythrityl tetranitrate-induced in vivo formation of superoxide radicals: effect of vitamin C.

Glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) are among the most known organic nitrates that are used in cardiovascular therapy as vasodilators. However, anti-ischemic therapy with organic nitrates is complicated by the induction of nitrate tolerance. When nitrates are metabolized to release nitric oxide (NO), there is considerable coproduction of superoxide radicals in vessels leading to inactivation of NO. However, nitrate-induced increase of superoxide radical formation in vivo has not been reported. In this work, the authors studied the in vivo formation of superoxide radicals induced by treatment with PETN or GTN and determined the antioxidant effect of vitamin C. The formation of superoxide radicals was determined by the oxidation of 1-hydroxy-3-carboxy-pyrrolidine (CP-H) to paramagnetic 3-carboxy-proxyl (CP) using electron spin resonance spectroscopy. CP-H (9 mg/kg intravenous bolus and 0.225 mg/kg per minute continuous intravenous GTN or PETN 130 microg/kg) were infused into anesthetized rabbits. Every 5 min, blood samples were obtained from Arteria carotis to measure the CP formation. Both PETN and GTN showed similar vasodilator effects. Formation of CP in blood after infusions of GTN and PETN were 2.0+/-0.4 microM and 0.98+/-0.23 microM, respectively. Pretreatment with 30 mg/kg vitamin C led to a significant decrease in CP formation: 0.27+/-0.14 microM (vitamin C plus GTN) and 0.34+/-0.15 microM (vitamin C plus PETN). Pretreatment of animals with superoxide dismutase (15,000 units/kg) significantly inhibited nitrate-induced nitroxide formation. Therefore, in vivo infusion of GTN or PETN in rabbits increased the formation of superoxide radicals in the vasculature. PETN provoked a minimal stimulation of superoxide radical formation without simultaneous development of nitrate tolerance. The data suggest that the formation of superoxide radicals induced by organic nitrate correlates with the development of nitrate tolerance. The effect of vitamin C on CP formation leads to the conclusion that vitamin C can be used as an effective antioxidant for protection against nitrate-induced superoxide radical formation in vivo.

Animals↗
PubMed2005

Phosphatidylinositol 4,5-bisphosphate regulates activation-induced platelet microparticle formation.

While the role of the cytoskeleton in microparticle formation is well-described, the role of membrane phospholipids in regulating this process is poorly defined. PIP(2) binds many cytoskeletal proteins and may oppose microparticle formation through associations with these proteins. To determine whether PIP(2) effects microparticle formation, PIP(2) was incorporated into platelet membranes prior to activation-induced microparticle formation. Incorporation of PIP(2) into platelet membranes inhibited activation-induced microparticle formation by >or=90%. Inhibition was dose-dependent with an IC(50) of 12-18 microM. A permeabilized platelet system was next used to assess the effect of modulation of endogenous PIP(2) levels on microparticle formation. Infusion of type IIbeta PIP kinase into permeabilized platelets inhibited microparticle formation by 75 +/- 8%. In contrast, incubation of permeabilized platelets with PI-specific phospholipase C augmented microparticle formation by greater than 3-fold. Evaluation of PIP kinases following platelet activation demonstrated that they were lost from platelets in a calpain-dependent manner during microparticle formation. Purified mu-calpain cleaved recombinant type IIbeta PIP kinase and inhibited its ability to phosphorylate PI(5)P. In permeabilized platelets, incubation of purified mu-calpain reduced PIP(2) levels, while exposure to calpeptin increased PIP(2) levels. Calpain has previously been implicated in platelet microparticle formation. These studies show that calpain may help limit PIP(2) formation following platelet activation and that PIP(2) content is an important determinant of platelet microparticle formation.

Blood Platelets↗
PubMed2000

The effect of sterol structure on membrane lipid domains reveals how cholesterol can induce lipid domain formation.

Detergent-insoluble membrane domains, enriched in saturated lipids and cholesterol, have been implicated in numerous biological functions. To understand how cholesterol promotes domain formation, the effect of various sterols and sterol derivatives on domain formation in mixtures of the saturated lipid dipalmitoylphosphatidylcholine (DPPC) and a fluorescence quenching analogue of an unsaturated lipid was compared. Quenching measurements demonstrated that several sterols (cholesterol, dihydrocholesterol, epicholesterol, and 25-hydroxycholesterol) promote formation of DPPC-enriched domains. Other sterols and sterol derivatives had little effect on domain formation (cholestane and lanosterol) or, surprisingly, strongly inhibit it (coprostanol, androstenol, cholesterol sulfate, and 4-cholestenone). The effect of sterols on domain formation was closely correlated with their effects on DPPC insolubility. Those sterols that promoted domain formation increased DPPC insolubility, whereas those sterols that inhibit domain formation decreased DPPC insolubility. The effects of sterols on the fluorescence polarization of diphenylhexatriene incorporated into DPPC-containing vesicles were also correlated with sterol structure. These experiments indicate that the effect of sterol on the ability of saturated lipids to form a tightly packed (i.e., tight in the sense that the lipids are closely packed with one another) and ordered state is the key to their effect on domain formation. Those sterols that promote tight packing of saturated lipids promote domain formation, while those sterols that inhibited tight packing of saturated lipids inhibited domain formation. The ability of some sterols to inhibit domain formation (i.e., act as "anti-cholesterols") should be a valuable tool for examining domain formation and properties in cells.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

The role of protein phosphorylation and cytoskeletal reorganization in microparticle formation from the platelet plasma membrane.

Platelets activated by various agonists produce vesicles (microparticles; MPs) from the plasma membrane. However, the mechanism of this MP formation remains to be elucidated. To investigate the possible involvement of protein phosphorylation and cytoskeletal reorganization in MP formation, the effects of various inhibitors on MP formation were investigated. Flow cytometry was employed to detect the amount of MP formation by using monoclonal antibodies against glycoprotein (GP) IIb-IIIa (NNKY 1-32) or GPIIb (Tab). The relationship between changes in cytoskeletal architecture and MP formation in the platelets activated by thrombin plus collagen was observed by scanning electron microscopy (SEM). MPs were observed in the vicinity of the terminals of pseudopods, suggesting that MPs may be related by budding of the pseudopods. Cytochalasin D (10 microM) inhibited MP formation from the activated platelets almost completely. Moreover, SEM of the cytochalasin D-treated platelets revealed the absence of shape change, pseudopod formation and MPs. These findings suggest that cytoskeletal reorganization is necessary for MP formation. Since cytoskeletal reorganization is considered to be regulated by a dynamic phosphorylation-dephosphorylation process, we investigated the effects of the protein phosphatase inhibitors, calyculin A (CLA) and okadaic acid (OA), on MP formation. Flow cytometry showed that these two inhibitors doubled MP formation in activated platelets. SEM of the platelets treated with CLA or OA demonstrated more prominent shape change and pseudopod formation in these platelets than in those without inhibitor. From these results, we conclude that cytoskeletal reorganization, which is controlled by phosphorylation, is involved in MP formation.

Adult↗
PubMed1997

Characterization of glutamate-induced formation of N-acylphosphatidylethanolamine and N-acylethanolamine in cultured neocortical neurons.

Glutamate-induced formation of N-acylethanolamine (NAE) and N-acylphosphatidylethanolamine (NAPE) was studied in primary cultures of mouse neocortical neurons prelabeled with [14C] ethanolamine. The formation of these two lipids was dependent on the maturity of the cell culture; i.e., no glutamate-induced formation was seen in 2-day-old cultures, whereas glutamate induced a pronounced formation in 6-day-old cultures. The calcium ionophore A23187 (2 microM) stimulated, within 2 h, formation of NAPE in 2-day-old cultures (fourfold) as well as in 6-day-old cultures (eightfold). Glutamate exerted its effect via NMDA receptors as seen by the inhibitory action of the NMDA-selective receptor antagonists D-(-)-2-amino-5-phosphonovalerate and N-(1-(2-thienyl)cyclohexyl)piperidine and the lack of effect of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate-receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In 6-day-old cultures, exposure to NMDA (100 microM for 24 h) induced a linear increase in the formation of NAPE and NAE as well as a 40-50% neuronal death, as measured by a decrease in cellular formazan formation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay]. The increase in NAPE and NAE could be detected earlier than the neuronal death. Neither cyclic AMP, cyclic GMP, nitric oxide, protein kinase C, nor peroxidation appears to be involved in the formation of NAPE and NAE, as assessed by the use of different pharmacological agents. Exposure to 5 mM NaN3 for 8 h resulted in a >80% decrease in the cellular MTT staining and a pronounced linear increase in the formation of NAE and NAPE (reaching 25-30% of total labeling). [14C]Anandamide was also formed in [14C]arachidonic acid-labeled neurons exposed to NaN3. No NAPE formation was detected in A23187-stimulated mouse astrocytes, rat Leydig cells and cardiomyocytes, and several other cells. These results suggest that the glutamate-induced formation of NAPE and NAE was mediated by the NMDA receptor and the formation of these lipids may be associated with neuronal death.

2-Amino-5-phosphonovalerate↗
PubMed2003

Osteopontin expression in osteoblasts and osteocytes during bone formation under mechanical stress in the calvarial suture in vivo.

UNLABELLED: To clarify the role of OPN in bone formation under mechanical stress, we examined the expression and the function of OPN in bone using an expansion force-induced osteogenesis model. Our results indicated that OPN expression was enhanced during the bone formation and that OPN would be one of the positive factors for the bone formation under mechanical stress. INTRODUCTION: Bone formation is known to be stimulated by mechanical stress; however, molecules involved in stress-dependent regulation of bone formation have not yet been fully characterized. Extracellular matrix proteins such as osteopontin (OPN) could play a role in mediation of the mechanical stress signal to osteoblasts. However, the function of OPN in bone formation under mechanical force is not known. Therefore, we examined the expression and the role of OPN in bone formation in vivo under tensile mechanical stress. MATERIALS AND METHODS: Sagittal sutures of mice were subjected to expansion mechanical stress by setting orthodontic spring wires, and OPN expression during bone formation within the suture gap was examined. RESULTS: Expansion of the sutures resulted in bone formation at the edges of the parietal bones within the sagittal suture. Immunohistochemical analysis revealed abundant accumulation of OPN protein in the matrix of newly formed bone on the inner edge of the parietal bone within the mechanically expanded sutures. Osteoblasts forming bone within the suture subjected to tensile stress also exhibited high levels of OPN protein expression. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis indicated that OPN mRNA expression was enhanced in wild-type calvariae subjected to expansion force compared with the control calvariae where dead spring wires were set without expansion stress. In addition, type I collagen mRNA was also expressed in the calvariae under the mechanical stimuli. To understand the function of OPN, sagittal sutures in OPN-deficient mice were subjected the expansion stress, and bone formation within the suture to fill the expanded gap was compared with that observed in wild-type mice. OPN deficiency reduced bone formation at the edge of the parietal bone in contact with the expanded suture gap. CONCLUSIONS: These observations revealed that OPN plays a pivotal role in bone formation under tensile mechanical stress.

Animals↗
PubMed2000

Hydrogen peroxide formation and decay in iron-rich geothermal waters: the relative roles of abiotic and biotic mechanisms

Hydrogen peroxide (H2O2) is widely distributed in surface waters where the primary photochemical formation pathway involves the interaction between dissolved organic carbon (DOC) and ultraviolet radiation (UVR). In laboratory studies using iron-rich water from Yellow-stone's Chocolate Pots spring, H2O2 formation depended on sample treatment (unfiltered, < 0.2 micron filtered, autoclaved) prior to irradiation, suggesting several formation pathways. Similar H2O2 formation in filtered and unfiltered water indicates that it is primarily soluble material that is responsible for H2O2 formation. H2O2 formation with soluble material probably includes only photochemical reactions with DOC and/or metals. Greater H2O2 formation in unfiltered and filtered water than in autoclaved water suggests that the agent(s) involved in H2O2 formation is (are) not stable at high temperatures and pressures and degrade to nonphotoreactive species. Such unstable agents may include DOC and/or dissolved complexes of iron or other metals. UVR absorbance occurs across the UV spectrum and, though slightly greater in the UVA range (320-400 nm), is similar to that of other surface waters. Increased UVR absorbance after autoclaving suggested degradation or alteration of some components, which in turn affected H2O2 formation. The spectral region used for irradiation affected net formation and yield. H2O2 formation in water irradiated with UVA radiation was 2.5-3 times that formed in water irradiated with UVB radiation (280-320 nm) in experiments using artificial light sources. Apparent quantum yields comparable to those reported by others could not be calculated because the instrumental designs are not the same. However, approximate quantum yields were calculated for these experiments but should be viewed with caution. Quantum yields were higher in these experiments (0.0040 mol H2O2 per mol photon at 310 nm and 0.0012 mol H2O2 per mol photon at 350 nm) than values reported by other researchers (< 0.0007 mol H2O2 per mol photon at 300 nm and < 0.0005 H2O2 per mol photon at 340 nm; [Scully, N. M., D. R. S. Lean, D. J. McQueen and W. J. Cooper (1996) Limnol. Oceanogr. 41, 540-548]). In natural solar source experiments, H2O2 formation was greater in experiments with UVA and photosynthetically active radiation (PAR; 400-700 nm) than with PAR alone or with UVB, UVA and PAR. However, H2O2 capacity (nM H2O2 W-1 h-1 m2) was greatest with UVB radiation and lowest with PAR radiation. Source regions could not be studied separately. Dark decay of H2O2 occurred via two mechanisms. The main mechanism responsible for H2O2 decay involved particulate matter (probably microorganisms), whereas a secondary mechanism involved soluble matter (i.e. DOC, metal ions and other dissolved species involved in Fenton reactions).

Journal Article↗
PubMed1994

The rate of cancellous bone formation falls immediately after ovariectomy in the rat.

We have recently found that administration of oestradiol-17 beta (OE2) to rats stimulates trabecular bone formation. It is not known, however, whether oestrogen has a similar action on bone formation rate under physiological circumstances. Oestrogen is known to suppress bone resorption, and oestrogen-deficient states in the rat, as in humans, are associated with an increase in bone resorption that entrains an increase in bone formation. To see if the latter masks a relative reduction in bone formation, due to oestrogen deficiency, we measured bone formation very early after ovariectomy, before the resorption-induced increase in bone formation becomes established. To do this, rats were administered fluorochrome labels before and after ovariectomy, spaced at weekly intervals in the first, and 3-day intervals in the second experiment. In both experiments there was a decrease in indices of bone formation in the labelling interval immediately following ovariectomy such that, using the shorter fluorochrome intervals, the mineral apposition rate fell to 69%, the double-labelled surface to 45%, and the bone formation rate to 36% of sham-ovariectomized levels. The reduction was not sustained in the subsequent label intervals, presumably masked by the increase in bone formation attributable to increased resorption. These results suggest that if bone formation is assessed before this resorption-entrained increase in bone formation occurs, oestrogen deficiency is associated with a reduction in dynamic indices of bone formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

SC-19220, a prostaglandin E2 antagonist, inhibits osteoclast formation by 1,25-dihydroxyvitamin D3 in cell cultures.

1,25 Dihydroxy vitamin D3 (1,25(OH)2D3), prostaglandin (PG) E2 and parathyroid hormone (PTH) induce osteoclast formation in cell cultures. Previously, we have shown that SC-19220, an antagonist of the EP1 subtype of PGE receptors, inhibited tartrate-resistant acid phosphatase (TRAP)-positive cell formation by PGE2 and PTH in adherent cell cultures taken from neonatal rats. Since 1,25(OH)2D3 has been shown to induce osteoclast formation through PGE2 synthesis, in this study we have examined the effect of SC-19220 on osteoclast formation induced by 1,25(OH)2D3 in cell cultures by measuring bone resorption as well as TRAP-positive cell formation. SC-19220 inhibited osteoclast formation by 1,25(OH)2D3 as well as by PGE2 in cell cultures. The addition of SC-19220 to the later half but not to the earlier half of the culture inhibited 1,25(OH)2D3-induced formation. In the culture in which hydroxyurea was added in the later half period, SC-19220 inhibited osteoclast formation by 1, 25(OH)2D3. Under these conditions, 17-phenyl PGE1, an EP1 agonist, induced osteoclast formation. Thus, SC-19220 inhibits certain reactions in the later processes of osteoclast formation induced by 1,25(OH)2D3. In addition, SC-19220 also inhibited osteoclast formation induced by interleukin (IL)-11 and IL-6 as well as by PTH. It is suggested that the SC-19220 inhibiting reactions are shared by all the inducers including 1,25(OH)2D3 and are essential for osteoclast formation.

Animals↗
PubMed1991

Differential inhibition of human neutrophil activation by cyclosporins A, D, and H. Cyclosporin H is a potent and effective inhibitor of formyl peptide-induced superoxide formation.

Cyclosporin (Cs)A but not CsH inhibits activation of human lymphocytes. We studied the effects of CsA, CsD, and CsH on human neutrophil activation induced by chemoattractants and by various substances that circumvent receptor stimulation. CsH inhibited superoxide (O2-) formation induced by the chemotactic peptide, FMLP (30 nM), with a half-maximal effect at 40 nM. O2- formation was abolished by CsH at 1 microM. CsH increased the concentration of FMLP causing half-maximal activation of O2- formation from 30 nM to 0.8 microM and substantially reduced the stimulatory effect of FMLP at supra-maximally effective concentrations. The inhibitory effect of CsH on O2- formation was evident immediately after addition to neutrophils. CsH also markedly inhibited the increase in cytosolic Ca2+ ([Ca2+]i), beta-glucuronidase, and lysozyme release and aggregation stimulated by FMLP. CsA and CsD were considerably less effective than CsH to inhibit FMLP-induced O2- formation. CsA and CsD were without effect on exocytosis, rises in [Ca2+]i, and aggregation induced by the chemotactic peptide. Cyclosporines inhibited FMLP-induced O2- formation in an additive manner, indicating that they acted through a mechanism they had in common. Cyclosporines only slightly inhibited O2- formation and lysozyme release induced by C5a. Aggregation and rises in [Ca2+]i stimulated by C5a were not affected by cyclosporines, and they did not inhibit O2- formation and exocytosis induced by platelet-activating factor and leukotriene B4. Cyclosporines partially inhibited O2- formations induced by NaF and gamma-hexachlorocyclohexane. CsA marginally inhibited PMA-induced O2- formation and lysozyme release. CsA, CsD, and CsH did not inhibit arachidonic acid-induced O2- formation and its potentiation by NaF or stable guanine nucleotides in a cell-free system from DMSO-differentiated HL-60 cells. CsH partially inhibited binding of FML [3H]P to formyl peptide receptors in membranes from DMSO- or dibutyryl cAMP-differentiated HL-60 cells. Our data show that: 1) cyclosporines differentially inhibit activation of human neutrophils; and 2) CsH is, indeed, not immunologically inactive but is a potent and effective inhibitor of FMLP-induced O2- formation. 3) CsH interferes with agonist binding to formyl peptide receptors and in addition, cyclosporines may also act at sites distal to chemoattractant receptors.

Bucladesine↗
PubMed1986

Activities derived from established human myeloid cell lines reverse the suppression of cell line colony formation by lactoferrin and transferrin.

Myeloid cell lines were evaluated for the release of substances needed for colony formation by their own colony-forming cells (CFC) and by other myeloid cell lines. Dialyzed U937 conditioned medium (CM) had no effect on the cloning efficiency of U937 cells, whether or not U937 CFC had been induced for MHC class-II antigens by preincubation of these cells for 72 h with indomethacin and human gamma interferon (HuIFN gamma). Dialyzed U937 CM, however, restored colony formation of HuIFN gamma-induced U937 cells suppressed by lactoferrin (LF) or transferrin (TF). Dialyzed U937 CM did not restore colony formation of U937 cells suppressed by acidic isoferritins (AIF) or prostaglandin E2 (PGE2). Detection of the growth-restoring effects of U937 CM required that U937 CM be prepared in the presence of indomethacin or that the CM be dialyzed to remove inhibitors of U937 colony formation. Dialyzed U937 CM did not inactivate LF. Dialyzed U937 CM did not stimulate or enhance colony formation of normal human bone marrow granulocyte-macrophage (CFU-GM), erythroid (BFU-E), or multipotential (CFU-GEMM) progenitor cells, but did contain potent inhibitory activity against these progenitor cells. HL-60, EM2, EM3, and K562 cells were also evaluated. HL-60-, EM3-, and K562-CFC that were not preincubated with HuIFN gamma did not express MHC class-II antigens, and colony formation by these cells was not influenced by LF, TF, or AIF. Noninduced EM2-CFC constitutively expressed MHC class-II antigens, and colony formation by these cells was suppressed by LF, TF, and AIF. After induction of MHC class-II antigens on HL-60- and EM3-CFC by HuIFN gamma, colony formation by these cells was suppressed by LF, TF, and AIF. Colony formation by HuIFN gamma-induced EM2 cells was more responsive to inhibition by LF, TF, and AIF than was colony formation by noninduced EM2 cells. K562 cells were not induced into a responsive state to LF, TF, or AIF by HuIFN gamma. Dialyzed CM from HL-60, EM2, and EM3 cells contained activities that restored colony formation by their own LF-suppressed CFC. The activities present in dialyzed CM from U937, HL-60, EM2, and EM3 cells may be similar since they could each restore LF-suppressed colony formation of U937, HL-60, EM2, or EM3 cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Line↗
PubMed1984

Hepatic and pulmonary microsomal metabolism of naphthalene to glutathione adducts: factors affecting the relative rates of conjugate formation.

Earlier studies demonstrating marked differences in the profile of polar metabolites formed during incubations of glutathione, naphthalene and microsomes from target (lung) and nontarget (liver and kidney) tissues of the mouse suggested that the formation of a particular reactive metabolite may be the underlying basis for the highly organ selective toxicity of this hydrocarbon. The studies reported here were done to characterize more fully the microsomal metabolism of naphthalene to 1,2-dihydro-1,2-dihydroxynaphthalene and to three glutathione-derived conjugates that were separated by high-pressure liquid chromatography. The microsomal formation of polar naphthalene metabolites was linear with time and microsomal protein; the relative proportions of each of the metabolites remained relatively stable over the range of time and protein concentrations studied. The rate of formation of naphthalene glutathione adducts, but not the dihydrodiol, was dependent upon the amount of 100,000 X g supernatant protein added. Addition of lung cytosol to liver microsomal incubations or liver cytosol to lung microsomal incubations altered the overall rate of conjugate formation but not the relative proportions of each of the three conjugate peaks. Epoxide hydrolase induction by dietary butylated hydroxyanisole or inhibition by cyclohexene oxide altered the rate of hepatic microsomal formation of naphthalene dihydrodiol in the expected manner and increased the production of conjugate peak 2. Butylated hydroxyanisole or cyclohexene oxide failed to alter the rate of formation of conjugate peak 1 or 3. Addition of piperonyl butoxide or SKF 525-A to hepatic microsomal incubations markedly decreased covalent binding of naphthalene metabolites but only slightly decreased glutathione adduct formation. Dihydrodiol formation was increased by both inhibitors. Phenobarbital or 3-methylcholanthrene pretreatment produced a marked increase in the pulmonary microsome-catalyzed formation of all four polar naphthalene metabolites. In comparison, phenobarbital increased the rates of formation of the dihydrodiol, conjugate peaks 1 and 2 but not 3 in hepatic microsomes. 3-Methylcholanthrene increased the rate of formation of the dihydrodiol and conjugate peak 2 but not 1 or 3. These studies indicate that the predominant formation of conjugate peak 2 in lung microsomal incubations in comparison to liver microsomal incubations is due to the regio- or stereoselectivity of naphthalene metabolism by cytochrome P-450 monooxygenases or epoxide hydrolases but not by the glutathione transferases.

Animals↗
PubMed1996

Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine.

The formation kinetics of 2-hydroxymethyl olanzapine (2-OH olanzapine), 4'-N-oxide olanzapine (N-O olanzapine) and 4'-N-desmethyl olanzapine (NdM olanzapine) were analyzed in vitro. Biphasic kinetics were observed for formation of 2-OH and NdM olanzapine. The high-affinity enzyme responsible for 2-OH olanzapine formation by two human liver samples exhibited an intrinsic clearance (CLint) of 0.2 microliter/min/mg. NdM olanzapine formation by two human liver samples exhibited a CLint of 1.0 microliter/min/mg for the high affinity enzyme. The formation of N-O olanzapine was linear up to 300 microM olanzapine, yielding a CLint of 0.32 to 1.70 microliters/min/mg. The formation of 7-hydroxy olanzapine (7-OH olanzapine) exhibited an apparent Km of 24.2 microM. The rates of 2-OH olanzapine formation correlated with CYP2D6 levels and activity, and it was formed to the greatest extent by cDNA-expressed CYP2D6. N-O olanzapine formation correlated with human liver flavin-containing monooxygenase (FMO3) levels and activity. NdM olanzapine and 7-OH olanzapine formation correlated with CYP1A2 catalytic activities and they were formed to the greatest extent by expressed CYP1A2. These results suggest that CYP1A2 catalyzes NdM olanzapine and 7-OH olanzapine formation, CYP2D6 catalyzes 2-OH olanzapine formation and FMO3 catalyzes N-O olanzapine formation.

Antipsychotic Agents↗
PubMed1998

Two distinct pathways mediate the formation of intermediate density cells and hyperdense cells from normal density sickle red blood cells.

In sickle cell anemia (SS), some red blood cells dehydrate, forming a hyperdense (HD) cell fraction (>1.114 g/mL; mean corpuscular hemoglobin concentration [MCHC], >46 g/dL) that contains many irreversibly sickled cells (ISCs), whereas other SS red blood cells dehydrate to an intermediate density (ID; 1.090 to 1.114 g/mL; MCHC, 36 to 46 g/dL). This study asks if the potassium-chloride cotransporter (K:Cl) and the calcium-dependent potassium channel [K(Ca2+)] are participants in the formation of one or both types of dense SS red blood cells. We induced sickling by exposing normal density (ND; 1.080 to 1.090 g/mL; MCHC, 32 to 36 g/dL) SS discocytes to repetitive oxygenation-deoxygenation (O-D) cycles in vitro. At physiologic Na+, K+, and Cl-, and 0.5 to 2 mmol/L Ca2+, the appearance of dense cells was time- and pH-dependent. O-D cycling at pH 7.4 in 5% CO2-equilibrated buffer generated only ID cells, whereas O-D cycling at pH 6.8 in 5% CO2-equilibrated buffer generated both ID and HD cells, the latter taking more than 8 hours to form. At 22 hours, 35% +/- 17% of the parent ND cells were recovered in the ID fraction and 18% +/- 11% in the HD fraction. Continuous deoxygenation (N2/5% CO2) at pH 6.8 generated both ID and HD cells, but many of these cells had multiple projections, clearly different from the morphology of endogenous dense cells and ISCs. Continuous oxygenation (air/5% CO2) at pH 6.8 resulted in less than 10% dense cell (ID + HD) formation. ATP depletion substantially increased HD cell formation and moderately decreased ID cell formation. HD cells formed after 22 hours of O-D cycling at pH 6.8 contained fewer F cells than did ID cells, suggesting that HD cell formation is particularly dependent on HbS polymerization. EGTA chelation of buffer Ca2+ inhibited HD but not ID cell formation, and increasing buffer Ca2+ from 0.5 to 2 mmol/L promoted HD but not ID cell formation in some SS patients. Substitution of nitrate for Cl- inhibited ID cell formation, as did inhibitors of the K:Cl cotransporter, okadaic acid, and [(dihydroindenyl) oxy]alkanoic acid (DIOA). Conversely, inhibitors of K(Ca2+), charybdotoxin and clotrimazole, inhibited HD cell formation. The combined use of K(Ca2+) and K:Cl inhibitors nearly eliminated dense cell (ID + HD cell) formation. In summary, dense cells formed by O-D cycling for 22 hours at pH 7.4 cycling are predominately the ID type, whereas dense cells formed by O-D cycling for 22 hours at pH 6.8 are both the ID and HD type, with the latter low in HbF, suggesting that HD cell formation has a greater dependency on HbS polymerization. A combination of K:Cl cotransport and the K(Ca2+) activities account for the majority of dense cells formed, and these pathways can be driven independently. We propose a model in which reversible sickling-induced K+ loss by K:Cl primarily generates ID cells and K+ loss by the K(Ca2+) channel primarily generates HD cells. These results imply that both pathways must be inhibited to completely prevent dense SS cell formation and have potential therapeutic implications.

Adenosine Triphosphate↗
PubMed1987

Factors affecting transcriptional regulation of the formate-hydrogen-lyase pathway of Escherichia coli.

The regulatory elements involved in expression of the gene (fdhF) for the selenopolypeptide of formate dehydrogenase and of a gene (or transcriptional unit) (hyd) specifically responsible for the formation of the gas-evolving hydrogenase (hydrogenase 3) in Escherichia coli were investigated. Formate (or a product of it) is required for expression of both systems since in a pyruvate-formate-lyase deficient mutant induction occurs only when formate is supplemented externally. Under this condition, formate can partially overcome repression by nitrate. The transcription of both the fdhF gene and the hydrogenase-3-encoding systems is independent of the presence of a wild-type fnr gene when formate is present, supporting the view that the Fnr effect on the formation of the formate-hydrogen-lyase pathway is indirect. Mutations blocking the synthesis of a functional molybdenum cofactor also had no major affect on fdhF and hyd expression. The nucleotide sequence of the 5' flanking region of the fdhF gene was determined and the transcription start point of the fdhF gene was localized by nuclease S1 mapping. Nuclease Bal31 generated deletion clones were constructed and the regulation of their expression was studied. Anaerobic expression and induction by formate depended on the presence of a stretch of approximately 185 nucleotides upstream of the translation start. Elements mediating formate induction and oxygen or nitrate repression could not be separated physically. The regulatory features of the fdhF upstream region bear striking resemblance to systems whose expression are dependent upon upstream activating elements.

Aldehyde Oxidoreductases↗
PubMed2000

Formate-induced inhibition of the water-oxidizing complex of photosystem II studied by EPR.

The effects of various formate concentrations on both the donor and the acceptor sides in oxygen-evolving PS II membranes (BBY particles) were examined. EPR, oxygen evolution and variable chlorophyll fluorescence have been observed. It was found that formate inhibits the formation of the S(2) state multiline signal concomitant with stimulation of the Q(A)(-)Fe(2+) signal at g = 1.82. The decrease and the increase in intensities of the multiline and Q(A)(-)Fe(2+) signals, respectively, had a linear relation for formate concentrations between 5 and 500 mM. The g = 4.1 signal formation measured in the absence of methanol was not inhibited by formate up to 250 mM in the buffer. In the presence of 3% methanol the g = 4.1 signal evolved as formate concentration increased. The evolved signal could be ascribed to the inhibited centers. Oxygen evolution measured in the presence of an electron acceptor, phenyl-p-benzoquinone, was also inhibited by formate proportionally to the decrease in the multiline signal intensity. The inhibition seemed to be due to a retarded electron transfer from the water-oxidizing complex to Y(Z)(+), which was observed in the decay kinetics of the Y(Z)(+) signal induced by illumination above 250 K. These results show that formate induces inhibition of water oxidation reactions as well as electron transfer on the PS II acceptor side. The inhibition effects of formate in PS II were found to be reversible, indicating no destructive effect on the reaction center induced by formate.

Chloroplasts↗
PubMed2006

Bridge-bonded formate: active intermediate or spectator species in formic acid oxidation on a Pt film electrode?

We present and discuss the results of an in situ IR study on the mechanism and kinetics of formic acid oxidation on a Pt film/Si electrode, performed in an attenuated total reflection (ATR) flow cell configuration under controlled mass transport conditions, which specifically aimed at elucidating the role of the adsorbed bridge-bonded formates in this reaction. Potentiodynamic measurements show a complex interplay between formation and desorption/oxidation of COad and formate species and the total Faradaic current. The notably faster increase of the Faradaic current compared to the coverage of bridge-bonded formate in transient measurements at constant potential, but with different formic acid concentrations, reveals that adsorbed formate decomposition is not rate-limiting in the dominant reaction pathway. If being reactive intermediate at all, the contribution of formate adsorption/decomposition to the reaction current decreases with increasing formic acid concentration, accounting for at most 15% for 0.2 M DCOOH at 0.7 VRHE. The rapid build-up/removal of the formate adlayer and its similarity with acetate or (bi-)sulfate adsorption/desorption indicate that the formate adlayer coverage is dominated by a fast dynamic adsorption-desorption equilibrium with the electrolyte, and that formate desorption is much faster than its decomposition. The results corroborate the proposal of a triple pathway reaction mechanism including an indirect pathway, a formate pathway, and a dominant direct pathway, as presented previously (Chen, Y. X.; et al. Angew. Chem. Int. Ed. 2006, 45, 981), in which adsorbed formates act as a site-blocking spectator in the dominant pathway rather than as an active intermediate.

Adsorption↗