Nitisinone. Ntbc, Orfadin.
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Cyclohexanones↗
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Multidrug resistance and anticonvulsants: new studies with some enaminones.
The multidrug resistance (MDR), often conferred by the active extrusion of drugs from the cell, is a phenomenon often seen in cancer cells that may become resistant to a wide spectrum of drugs with varying chemical structures or cellular targets. This event has recently been reported for anticonvulsants. Studies in our laboratories on this occurrence with some enaminones have shown that the enaminones display high efflux ratios and are recognized by P-glycoprotein (P-gp) and/or the multidrug resistance protein (MRP), which have been reported as the main efflux transporters responsible for the development of MDR. Recent studies have uncovered interesting structural analogues that can modulate the functional activity of P-gp, suggesting a possible increase in the bioavailabillity of P-gp substrate drugs when administered concurrently.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Participation of glucokinase inactivation in inhibition of glucose-induced insulin secretion by 2-cyclohexen-1-one.
We assessed our speculation that 2-cyclohexen-1-one (CHX) impairs glucose-induced insulin secretion through inactivation of glucokinase. Treatment of pancreatic islets with CHX at concentrations (0-5 mM) that caused a dose-dependent inactivation of glucokinase activity similarly inhibited glucose-induced insulin secretion. Another glucose-phosphorylating enzyme (hexokinase) in pancreatic islets was little affected by CHX. CHX-induced inactivation of glucokinase was blocked by the presence of its substrates (glucose and mannose) and an inhibitor (N-acetylglucosamine), all of which also protected against the inhibitory effect of the drug on glucose-induced insulin secretion. CHX also impaired insulin secretion induced by D-glyceraldehyde and dimethyl succinate, which are believed to stimulate the release of the hormone by being directly oxidized by glyceraldehyde-3-phosphate dehydrogenase, by entering the midstream of the glycolytic pathway as glyceraldehyde 3-phosphate, or by entering the tricarboxylic acid cycle in mitochondria after intracellular hydrolysis. The inhibitory effect of CHX on glucose-induced insulin secretion, however, was far more marked than that on insulin secretion evoked by D-glyceraldehyde and dimethyl succinate at any CHX concentrations used. Our study revealed that the inhibitory action of CHX on glucose-induced insulin secretion is exerted mainly, but not solely, through inactivation of glucokinase. This conclusion supports the view that glucokinase is a key enzyme in the recognition of glucose as an insulin secretagogue in pancreatic islets.
Animals↗
Dual functional role of membrane depolarization/Ca2+ influx in rat pancreatic B-cell.
Transient exposure of rat pancreatic B-cell to 50 mM K+ ([K+50]) makes exocytosis unresponsive to further depolarization, i.e., stimulation with 100 mM K+ or 1 uM glyburide, which closes the ATP-sensitive K+ (K+ATP) channel, simultaneously with [K+50] does not produce any greater insulin secretion compared with [K+50] alone. In sharp contrast, 16.7 mM glucose ([G16.7]) applied simultaneously with [K+50] elicits an insulin response markedly greater than that produced by [K+50] alone, which is not attenuated by 100 uM diazoxide, an inhibitor of K+ATP channel closure. [G16.7]-induced insulin secretion at the basal K+ concn of 4.7 mM was greatly (93%) suppressed by 100 uM diazoxide. Insulin secretion induced by [K+50] plus [G16.7] ([K+50 + G16.7]) was markedly suppressed (70%) by 1 uM nifedipine, a Ca(2+)-channel blocker and was completely abolished by 2 mM 2-cyclohexen-1-one, which reportedly decreases reduced glutathione level and blocks glucokinase. This finding indicates that insulin release induced by [K+50 + G16.7] is not due to leakage produced by toxic stimuli but to activation of exocytosis. When graded concentrations (25 and 50 mM) of K+ were applied simultaneously with [G16.7] in the presence of 100 uM diazoxide, insulin response was clearly dependent on K+ concentration, indicating that the physiological range of membrane depolarization also activates the glucose-responsive effector. Membrane depolarization/Ca2+ influx directly stimulates hormone exocytosis on one hand and activates the K+ATP channel-independent glucose-responsive effector or effectors on the other in the B-cell. The nature of the glucose-responsive effector or effectors remains to be established.
Adenosine Triphosphate↗
Hexobarbital metabolism: a new metabolic pathway to produce 1,5-dimethylbarbituric acid and cyclohexenone-glutathione adduct via 3'-oxohexobarbital.
1. In the presence of glutathione under physiological conditions, 3'-oxohexobarbital was non-enzymically converted to 1,5-dimethylbarbituric acid and a cyclohexenone-glutathione adduct. 2. The two reaction products were characterized by mass spectrometry, 1H- and 13C-n.m.r. spectrometry, and UV spectral analyses. 3. 1,5-Dimethylbarbituric acid was excreted in urine of rat given hexobarbital, 3'-oxohexobarbital, or 1',2'-epoxyhexobarbital, and accounted for 13.4, 14.5 and 4.7% of dose, respectively. 4. The cyclohexenone-glutathione adduct, a novel metabolite of hexobarbital, was excreted in the bile of rat given hexobarbital. 5. The route of 1,5-dimethylbarbituric acid formation via 3'-oxohexobarbital in the metabolism of hexobarbital was discussed in comparison with the epoxide-diol pathway.
Animals↗
Murine cytochrome P4503A is induced by 2-methyl-3-buten-2-ol, 3-methyl-1-pentyn-3-ol(meparfynol), and tert-amyl alcohol.
1. Colupulone, a constituent of hops, was shown to be a potent inducer of hepatic P4503A in mouse. The olefin, 2-methyl-3-buten-2-ol (RC = CH2), is formed from lupulones when hops are exposed to atmospheric hydroxyl radicals. This suggested the possibility that the same reaction may occur in vivo. The credibility of this hypothesis was enhanced when RC = CH2 was shown to induce P4503A in mouse. Ethylmorphine (EM) N-demethylation, a functional marker for P4503A, was also induced by RC = CH2. 2. 3-Methyl-1-pentyn-3-ol (RC identical to meparfynol), a sedative and close structural analogue of RC = CH2, also induced P4503A and EM N-demeythylation. Tert-amyl alcohol (RC-CH3), the saturated analogue of RC = CH2, was included in t he study with the expectation that it would serve as a negative control for the anticipated induction of P4503A by the other two alcohols. This proved not to be the case; RC-CH3 was about as active an inducer of P4503A as RC = CH2 and RC identical to CH. The possibility is considered that, like valproic acid, RC-CH3 is metabolized to an olefin by P450. 3. Hydroxylation of aniline and benzo[a]pyrene by hepatic microsomes from mice treated with the three alcohols were used as functional markers for the induction of P4502E and P4501A respectively. RC = CH2 at the two lowest levels of administration suppressed aniline hydroxylation but had no effect at the highest level. RC identical to CH was ineffective and RC-CH3 was moderately inductive at all three levels. Each of the three compounds were weak to moderate inducers of benzo[a]pyrene hydroxylation.
Aniline Compounds↗
Hereditary tyrosinaemia type I: from basics to progress in treatment.
Hereditary tyrosinaemia type I is the most common of the diseases caused by defects in tyrosine metabolism. The underlying genetic defect is a mutation in the gene for fumarylacetate hydrolase (FAH), and more than 30 different mutations in this gene have been identified. The main clinical consequences of this defect include hepatic involvement, with a high risk for liver cancer, and renal tubular dysfunction. Restriction of phenylalanine and tyrosine from the diet along with supportive measures can ameliorate the symptoms, but cure has so far been possible only with liver transplantation. Recent discovery of a pharmacological treatment with a peroral inhibitor of tyrosine catabolic pathway, 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), offers a new promising tool for the treatment of patients with hereditary tyrosinaemia type I. Mouse models of FAH deficiency have been successfully used in experimental gene therapy, and these studies indicate that future management of tyrosinaemia with a gene therapeutic approach may become feasible.
Animals↗
Dimedone as an aldehyde blocking reagent to facilitate the histochemical demonstration of glycogen.
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Abstracting and Indexing↗
The influence of superoxide on the production of hypochlorous acid by human neutrophils.
Human neutrophils stimulated with opsonized zymosan promoted hypochlorous acid (HOCl)-dependent loss of monochlorodimedon. Formation of HOCl was completely inhibited by catalase, and it was also inhibited up to 70% by SOD. There was no inhibition by desferal, DTPA, mannitol or dimethylsulphoxide, which excluded the involvement of .OH. Our results indicate that generation of O2- by neutrophils enables these cells to enhance their production of HOCl. Furthermore, inhibition of neutrophil processes by SOD and catalase does not necessarily implicate .OH. We propose that O2- may potentiate oxidant damage at inflammatory sites by boosting the myeloperoxidase-dependent production of HOCl.
Catalase↗
Resonance Raman spectroscopy of chemically modified hemoglobins.
Hemoglobin obtained from out-dated human blood was stripped of 2,3-diphosphoglycerate and modified with the crosslinking agents glyoxalic acid, 1,2-cyclohexadione, or fumarate to stabilize the tetramer. The resulting hemoglobins, which show alterations in their oxygen transport capability, have been studied in their oxy, deoxy and fluoro-met forms using resonance Raman spectroscopy with Soret excitation. The resonance Raman spectra of oxy-hemoglobins cross linked with glyoxalic acid and 1,2-cyclohexadione show that these cross linking agents force the heme into a high spin structure. The resonance Raman spectra of the fluoro-met hemoglobins, however, indicate that the same cross linking agents force the heme into a lower spin structure. Absorption spectroscopy and molecular orbital considerations suggest that protein constraints at the sixth ligand of the heme can account for the change in spin state in the glyoxalic acid and 1,2-cyclohexadione cross linked hemoglobins.
Blood Substitutes↗
[Determination of isophorone in foods].
Isophorone (ISP) is used widely as a solvent of natural and synthetic resins, wax, printing ink, pesticides and paints. In this study, the level of ISP in various foods (93 samples) was analyzed. ISP was collected from samples by steam distillation after the addition of an internal standard, deuterium-labeled ISP, then extracted with dichloromethane, cleaned up on a silica gel column, and determined by GC/MS. ISP was barely detected in fish, meat and vegetable samples, but it was detected in rice, wheat, beans and their processed products, miso, soy sauce and fermented soybeans (natto). The maximum level was 8.9 ng/g in miso. The packaging materials of the foods contained little ISP, and so the source of ISP in the foods could not be clarified.
Cyclohexanones↗
ON THE BIOSYNTHESIS OF SPINULOSIN IN PENICILLUM SPINULOSUM.
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Aspergillus↗
The importance of arginyl residues for phosphorylation of rat liver cell sap proteins.
Arginyl residues in phosvitin, histone and cell sap protein were blocked by 1,2-cyclohexanedione, resulting in markedly impaired phosphorylation of histone and cell sap. Interestingly, the phosphate incorporation into phosvitin was not changed by this treatment. Intact arginyl residues in the protein kinase substrates seemed to be essential for more than half of the cell sap phosphorylation at 5 mM ATP. Furthermore both phosvitin kinase and histone kinase activities in cell sap were inhibited by arginyl residue blockade, indicating that these enzymes had functional arginyl residues.
Adenosine Triphosphate↗
Chemical studies of tissue polypeptide antigen (TPA). III. on the nature of the antigenic determinant(s) of TPA subfraction B1.
Tissue Polypeptide Antigen (TPA)*** which is a protein isolated from e.g. human carcinoma cells, has previously been separated into subfractions and studied with biochemical methods. Gel diffusion studies show that the antigenic determinants are retained through the isolation and purification procedures. Specific modifications of the amino acid residues lysine, tyrosine, trytophan and arginine in subfraction B1 have been related to the change in the capacity of the antigen to bind to horse anti-HeLa serum. Complete although reversible loss of binding capacity resulted from blocking of arginine and a minor loss was noted upon modification of tyrosine. No measurable influence was noted upon modification of lysine or tryptophan. No cysteine has been detected in subfraction B1. Circular dichroism measurements show that TPA subfraction B1 is largely alpha-helical in solution, and that no correlation could be detected between antigenic activity and conformation.
Acylation↗
Total synthesis of C31-methyl ketone apocarotenoids. 3. On the structure of hopkinsiaxanthin: first total synthesis of (all-E)-(3S)- and (9Z)-(3S)-7'-apohopkinsiaxanthin.
Optically active (all-E)-(3S)-7'-apohopkinsiaxanthin, previously known as F1, and (9Z)-(3S)-7'-apohopkinsiaxanthin have been prepared by total synthesis for the first time in ca. 1% combined overall yield, including two unidentified geometrical isomers, in sixteen linear steps from (4R,6R)-actinol, (2E)-3-methyl-2-penten-4-yn-1-ol, (7-formyl-2-methyl-2,4,6-octatrienyl)triphenylphosphonium bromide, (3-formyl-2-butenyl)triphenylphosphonium bromide and methyllithium, by use of a C15 + C10 + C5 + C1 approach. By an alternative route from (2Z)-5-[((4S)-4-hydroxy-2,6,6-trimethyl-3-oxo-1-cyclohexenyl)-3- methyl-2-penten-4-ynyl]triphenylphosphonium bromide, (7-formyl-2-methyl-2,4,6-octatrienyl)triphenylphosphonium bromide and (2E)-3-methyl-4-oxo-2-pentenal, the same target compounds were obtained in a combined overall yield of > 61%, including four unidentified geometrical isomers, over two steps, by use of a C15 + C16 approach. A hypothetical structure for hopkinsiaxanthin is discussed, based on present and previously reported spectroscopic and chemical data for (all-E)-(3S)- and (9Z)-(3S)-7'-apohopkinsiaxanthin and on data previously reported for hopkinsiaxanthin itself.
Chromatography↗
New initiator system for bonding to dentin using methylcyclohexanedione.
As a part of a series of studies to examine the role of the initiator system in dentin bonding, the effectiveness of a new polymerization initiator system consisting of 2-methyl-1,3-cyclohexanedione (MCHD) and CuCl2 in dentin bonding was investigated in terms of the effects of dentin conditioners and CuCl2 concentration formulated in MMA/PMMA resins. Curing time and tensile bond strength to bovine dentin were measured using resins composed of MMA containing 0.001-0.03 wt% CuCl2 and PMMA powder containing 2 wt% MCHD. The dentin surfaces were treated with six conditioners consisting of 10 wt% phosphoric acid or citric acid containing 0-3 wt% FeCl3 or CuCl2. The bond strengths of about 10 MPa obtained under optimal conditions were comparable to those reported for tributylborane-initiated MMA resin which is one of the most effective bonding resins available. Thus, the resin using MCHD/CuCl2 system was concluded to be very effective for dentin bonding, especially when dentin was treated with acidic conditioners containing ferric or copper chloride.
Animals↗
ECH, an epoxycyclohexenone derivative that specifically inhibits Fas ligand-dependent apoptosis in CTL-mediated cytotoxicity.
CTL eliminate cells infected with intracellular pathogens and tumor cells by two distinct mechanisms mediated by Fas ligand (FasL) and lytic granules that contain perforin and granzymes. In this study we show that an epoxycyclohexenone derivative,(2R,3R,4S)-2,3-epoxy-4-hydroxy-5-hydroxymethyl-6-(1E)-propenyl-cyclohex-5-en-1-one (ECH) specifically inhibits the FasL-dependent killing pathway in CTL-mediated cytotoxicity. Recently, we have reported that ECH blocks activation of procaspase-8 in the death-inducing signaling complex and thereby prevents apoptosis induced by anti-Fas Ab or soluble FasL. Consistent with this finding, ECH profoundly inhibited Fas-mediated DNA fragmentation and cytolysis of target cells induced by perforin-negative mouse CD4+ CTL and alloantigen-specific mouse CD8+ CTL pretreated with an inhibitor of vacuolar type H+-ATPase concanamycin A that selectively induces inactivation and proteolytic degradation of perforin in lytic granules. However, ECH barely influenced perforin/granzyme-dependent DNA fragmentation and cytolysis of target cells mediated by alloantigen-specific mouse CD8+ CTL. The components of lytic granules and the granule exocytosis pathway upon CD3 stimulation were also insensitive to ECH. In conclusion, our present results demonstrate that ECH is a specific nonpeptide inhibitor of FasL-dependent apoptosis in CTL-mediated cytotoxicity. Therefore, ECH can be used as a bioprobe to evaluate the contributions of two distinct killing pathways in various CTL-target settings.
Animals↗
A selective NFkappaB inhibitor, DHMEQ, reduced atherosclerosis in ApoE-deficient mice.
BACKGROUND AND PURPOSE: Atherosclerosis is a chronic inflammatory process, and anti-inflammatory agents potentially inhibit the development of atherosclerosis. We tested whether a novel NFkappaB inhibitor reduces atherosclerosis. METHODS: Dehydroxymethylepoxyquinomicin (10 mg/kg) or vehicle (chloromethyl cellulose) was injected intraperitoneally into apoE-deficient mice three times a week for 16 weeks. The entire aorta was excised and atherosclerotic area was determined at 4 and 16 weeks. Serum levels of cholesterol, triglyceride, TNF-alpha and adiponectin were also measured. RESULTS: The atherosclerotic area was significantly smaller in mice treated with dehydroxymethyl-epoxyquinomicin both at 4 and 16 weeks. There was no significant difference in body weight or serum levels of cholesterol, triglyceride, and adiponectin. CONCLUSIONS: A new NFkappaB inhibitor, dehydroxymethylepoxyquinomicin, reduced atherosclerosis without affecting plasma lipid levels in apoE-deficient mice.
Adiponectin↗