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PubMed2002

Metabolism of quercetin and kaempferol by rat hepatocytes and the identification of flavonoid glycosides in human plasma.

1. The metabolism of the flavonoids quercetin and kaempferol by rat hepatocytes was investigated using liquid chromatography coupled with electrospray mass spectrometry (LC-ESI MS). Quercetin and kaempferol were extensively metabolized (98.8 +/- 0.1% and 81.0 +/- 5.1% respectively, n = 4), with four glucuronides of quercetin and two of kaempferol being detected after incubation. 2. The glucuronides of quercetin and kaempferol formed upon incubation with rat hepatocytes were identified as the same ones formed after incubation with the UDP-glucuronosyltransferase isoform UGT1A9. 3. In addition, plasma samples from human volunteers taken after consumption of capsules of Ginkgo biloba, a plant rich in flavonoid glycosides, were analysed by LC-MS for the presence of flavonoid glucuronides and flavonoid glycosides. Reported is evidence for the presence of flavonoid glycosides in samples of plasma. 4. The results suggest that UGT1A9 is a key UDP-glucuronosyltransferase isoform for the metabolism of flavonoids, and that absorption of intact flavonoid glycosides is possible.

Adult↗
PubMed1984

Evidence for two kinetically and functionally different types of cardiac glycoside receptors in the heart.

Cardiac glycosides bind with high affinity to specific receptors in the heart. In cardiac cell membranes of most animal species and man, this glycoside-receptor binding is followed by a subsequent inhibition of the membrane-bound (Na+ + K+)-ATPase, the biochemical equivalent of the active Na+/K+-transport system. Most investigators, however, have been unable to find, as a consequence of the glycoside-(Na+ + K+)-ATPase interaction, an inhibited Na+ or K+ transport in intact cardiac tissue when using low but positive inotropic concentrations of cardiac glycosides. In electrically stimulated contracting rat or guinea pig cardiac muscle we determined two kinetically different 3H-ouabain binding sites. The high affinity/low capacity site is related to positive inotropy, whereas the low affinity/high capacity binding site is connected to an inhibition of the (Na+ + K+)-ATPase. Occupation of the low affinity sites with ouabain molecules was concomitant with an increased intracellular Na+ and loss of K+ as well as onset of arrhythmias. According to our experiments, there are at least two different types of ouabain binding sites, inhibition of the (Na+ + K+)-ATPase was not necessarily related to positive inotropy in rat and guinea pig heart.

Animals↗
PubMed2006

Cloning and biochemical characterization of the fucanase FcnA: definition of a novel glycoside hydrolase family specific for sulfated fucans.

Sulfated fucans are matrix polysaccharides from marine brown algae, consisting of an alpha-L-fucose backbone substituted by sulfate-ester groups, masked with ramifications, and containing other monosaccharide residues. We here report on the characterization of a novel glycoside hydrolase (FcnA) specific for the degradation of sulfated fucans. This glycoside hydrolase was purified to electrophoretic homogeneity from a Flavobacteriaceae referred to as SW5. The gene fcnA was cloned and sequenced (3021 nucleotides), and the protein (1007 amino acids) was produced in Escherichia coli. FcnA exhibited a modular architecture consisting of a 400-residue-long N-terminal domain followed by three repeated domains predicted to adopt an immunoglobulin fold and by an 80-amino acid-long C-terminal domain. A truncated recombinant protein encompassing the N-terminal domain and the immunoglobulin-like repeats was shown to retain the enzyme activity. The N-terminal catalytic domain shared approximately 25% of sequence identity with two patented fucanase genes, and these three fucanases delineate a new family of glycoside hydrolases. As shown by size-exclusion chromatography (SEC) and 1H-NMR analyses, the fucanase FcnA proceeds according to an endolytic mode of action and cleaves the alpha-(1-->4) glycosidic linkages within the blocks of repeating motifs [-->4)-alpha-L-fucopyranosyl-2,3-disulfate-(1-->3)-alpha-L-fucopyranosyl-2-sulfate-(1-->]n.

Amino Acid Sequence↗
PubMed1976

Kinetics of active sodium transport in rat proximal tubules and its variation by cardiac glycosides at zero net volume and ion fluxes. Evidence for a multisite sodium transport system.

1. Transepithelial Na concentration difference, deltaCNa, across proximal tubules of rat kidney was measured at varying intraluminal Na concentrations (CNainfinity) under conditions of zero net volume and Na flux. Simultaneous stopped-flow intratubular and artificial peritubular capillary perfusion techniques were used together with intratubular raffinose to achieve zero net fluxes. Under these conditions in rat proximal tubules, deltaCNa represents active transport, JactNa, factored by permeability, PNa, plus an electrical factor depending on transepithelial potential difference. 2. The relationship between CNainfinity and deltaCNa appeared sigmoidal with saturation being reached when intratubular Na was above 80 m-mole/kg. In the presence of ouabain (10(-2)M) and scilliroside (10(-3)M) the relationship remained the same. The maximum deltaCNa was reduced by approximately 50% by cardiac glycoside inhibition whereas the half-saturation constant was essentially unchanged. These changes from the control represent simple non-competitive inhibition by the cardiac glycosides. 3. Absence of potential difference (p.d.) measurements precludes exact description of the relation between true active transport and substrate concentration but much evidence indicates that the apparently sigmoid relation in the presence and absence of cardiac glycoside inhibition, would be retained if correction of deltaCNa values were possible. Such results could then be explained if there are at least three or more sites for Na on the pump system, of which at least two are not cardiac glycoside sensitive. They would also unequivocally exclude the presence of a single-site single-pump system or the simple algebraic addition of two such units since the kinetic curves for both would be hyperbolic rather than sigmoidal.

Animals↗
PubMed1994

The effect of cardiac glycosides on the Na+ pump current-voltage relationship of isolated rat and guinea-pig heart cells.

1. Whole-cell recording from isolated rat and guinea-pig ventricular myocytes revealed a change of the cardiac Na+ pump current (Ip)-voltage (V) relationship by cardiac glycosides, specific inhibitors of the Na(+)-K+ pump. 2. Dihydro-ouabain (DHO) diminished Ip in rat ventricular cells at 0 mV in a concentration-dependent manner. 3. The concentration-response curve of Ip inhibition caused by DHO was shifted to higher [DHO] at higher extracellular K+ concentrations ([K+]o) or at more negative membrane potentials. 4. In rat myocytes, DHO immediately flattened the normalized cardiac Ip-V curve and evoked or enhanced a region of negative slope. 5. Ouabain, at concentrations which caused a comparable inhibition of Ip, exerted DHO-like effects on the Ip-V relationship of rat ventricular myocytes. However, the effects developed more slowly. 6. A slowly developing alteration of the Ip-V curve was also observed upon application of DHO to guinea-pig ventricular cells. The range of [DHO] used was about 100-fold lower than that applied to rat ventricular cells, but was equally effective for Ip inhibition. 7. Increasing the K+ concentration of DHO-containing media affected the existing equilibrium of DHO binding to the cardiac Na(+)-K+ pump. A new equilibrium was reached within about 3 s in rat ventricular myocytes, but only within about 50 s in guinea-pig ventricular cells under the experimental conditions chosen. 8. It is concluded that the changes of the cardiac Ip-V curve induced by cardiac glycosides are mediated by voltage-dependent variations of the local [K+]o at the K+ binding sites of the Na(+)-K+ pump in an 'access channel'. The variations were estimated by means of the Boltzmann equation. The estimations agreed with those derived from the measured DHO binding to the Na(+)-K+ pump at various [K+]o. A new equilibrium of glycoside binding to the pump is established at the altered [K+]o. The time necessary to reach the new binding equilibrium varies with the cardioactive steroid, its concentration and the glycoside sensitivity of the cardiac cells.

Animals↗
PubMed2006

Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking.

Direct block of the cardiac potassium channel human ether-a-go-go-related gene (hERG) by a large, structurally diverse group of therapeutic compounds causes drug-induced QT prolongation and torsades de pointes arrhythmias. In addition, several therapeutic compounds have been identified more recently that prolong the QT interval by inhibition of hERG trafficking to the cell surface. We used a surface expression assay to identify novel compounds that interfere with hERG trafficking and found that cardiac glycosides are potent inhibitors of hERG expression at the cell surface. Further investigation of digitoxin, ouabain, and digoxin revealed that all three cardiac glycosides reduced expression of the fully glycosylated cell surface form of hERG on Western blots, indicating that channel exit from the endoplasmic reticulum is blocked. Likewise, hERG currents were reduced with nanomolar affinity on long-term exposure. hERG trafficking inhibition was initiated by cardiac glycosides through direct block of Na(+)/K(+) pumps and not via off-target interactions with hERG or another closely associated protein in its processing or export pathway. In isolated guinea pig myocytes, long-term exposure to 30 nM of the clinically used drugs digoxin or digitoxin reduced hERG/rapidly activating delayed rectifier K(+) current (I(Kr)) currents by approximately 50%, whereas three other cardiac membrane currents--inward rectifier current, slowly activating delayed rectifier K(+) current, and calcium current--were not affected. Importantly, 100 nM digitoxin prolonged action potential duration on long-term exposure consistent with a reduction in hERG/I(Kr) channel number. Thus, cardiac glycosides are able to delay cardiac repolarization at nanomolar concentrations via hERG trafficking inhibition, and this may contribute to the complex electrocardiographic changes seen with compounds such as digitoxin.

Action Potentials↗
PubMed2006

Physiological role of the alpha1- and alpha2-isoforms of the Na+-K+-ATPase and biological significance of their cardiac glycoside binding site.

An interesting feature of Na+-K+-ATPase is that it contains four isoforms of the catalytic alpha-subunit, each with a tissue-specific distribution. Our laboratory has used gene targeting to define the functional role of the alpha1- and alpha2-isoforms. While knockout mice demonstrated the importance of the alpha1- and alpha2-isoforms for survival, the knockin mice, in which each isoform can be individually inhibited by ouabain and its function determined, demonstrated that both isoforms are regulators of cardiac muscle contractility. Another intriguing aspect of the Na+-K+-ATPase is that it contains a binding site for cardiac glycosides, such as digoxin. Conservation of this site suggests that it may have an in vivo role and that a natural ligand must exist to interact with this site. In fact, cardiac glycoside-like compounds have been observed in mammals. Our recent study demonstrates that the cardiac glycoside binding site of the Na+-K+-ATPase plays a role in the regulation of blood pressure and that it mediates both ouabain-induced and ACTH-induced hypertension in mice. Whereas chronic administration of ouabain or ACTH caused hypertension in wild-type mice, it had no effect on blood pressure in mice with a ouabain-resistant alpha2-isoform of Na+-K+-ATPase. Interestingly, animals with the ouabain-sensitive alpha1-isoform and a ouabain-resistant alpha2-isoform develop ACTH-induced hypertension to a greater extent than wild-type animals. Taken together, these results demonstrate that the cardiac glycoside binding of the Na+-K+-ATPase has a physiological role and suggests a function for a naturally occurring ligand that is stimulated by administration of ACTH.

Animals↗
PubMed1981

Preferential sensitivity of the left canine purkinje system to cardiac glycosides.

Previous studies have shown that the toxic effects of cardiac glycosides are not manifested uniformly throughout the myocardium. The purpose of our study was to determine whether cardiac glycosides exert different effects on the right vs. left peripheral Purkinje systems and to ascertain mechanisms involved. Control in vitro measurements of paired right and left canine Purkinje fibers showed higher spontaneous rates in left (24.2 +/- 1.75 beats/min) than in right (11.6 +/- 1.55 beats/min, P less than 0.01, n = 81) Purkinje fiber bundles. Following overdrive stimulation, left Purkinje fiber bundles also showed earlier escape beats. After ouabain exposure (2 X 10-7 M), left Purkinje fiber bundles showed earlier signs of toxicity in 20 of 28 experiments, as determined by changes in the maximum diastolic potential, the degree of diastolic depolarization, spontaneous escape intervals, and the magnitude of delayed after-depolarizations. The enhanced sensitivity of left Purkinje fiber bundles was independent of the extracellular potassium concentration and glycoside polarity, and was also observed in situ. We conclude that distal Purkinje fibers are functionally dissimilar and that the left Purkinje system shows greater sensitivity to cardiac glycosides than the right Purkinje system. These data also support the observation that digitalis-induced dysrhythmias arise in the left ventricle.

Action Potentials↗
PubMed1998

Seasonal variation of glycyrrhizin and isoliquiritigenin glycosides in the root of Glycyrrhiza glabra L.

The time courses of the glycyrrhizin and isoliquiritigenin glycoside contents in the thickening roots of licorice, Glycyrrhiza glabra L., have been determined. The glycyrrhizin content in 1-year-old roots rapidly increased from October to November, whereas the isoliquiritigenin glycoside content increased up to October. In 3-year-old plants, although the isoliquiritigenin glycoside content rapidly increased from June to July, the glycyrrhizin content did not show any significant increase from May to August. The glycyrrhizin content increased during the senescence of the aerial parts as well as during the early stage of shoot elongation. The incorporation of [14C]mevalonic acid into the glycyrrhizin fraction by the root segments was high in May, June and September, and low in August and winter. These results indicated that the biosynthesis of glycyrrhizin is differently regulated from that of isoliquiritigenin glycoside in the thickening root of G. glabra.

Carbon Radioisotopes↗
PubMed2000

Anti-herpes virus activity of Solanum steroidal glycosides.

Since some Solanum-genus plants have traditionally been used for anti-cancer and anti-herpes agents from olden times, we examined anti-herpes simplex virus type 1 (HSV-1) activity of typical steroidal glycosides with the frameworks of spirostane (including nuatigenin glycoside), furostane, solasodane, tomatidane and ergostane (including dimer) obtained from Solanum plants. Among these steroidal glycosides, the spirostanol glycosides were most effective. An inclination was observed for the potency of activity to decrease in the order of spirostane, tomatidane, ergostane, solasodane, nuatigenin type, dimer of ergostane and furostane. It was also suggested that the activity depends on the kind of oligosacchride moiety.

Animals↗
PubMed2003

Cytotoxic activity of steroidal glycosides from solanum plants.

Since some Solanum-genera plants have traditionally been used as anti-cancer and anti-herpes agents from olden times, we examined the cytotoxic activity of typical steroidal glycosides with the framework of spirostane, furostane, spirosolane, and pregnane obtained from Solanum plants. Among these steroidal glycosides, the spirostanol glycosides having a beta-lycotetraosyl moiety were the most effective against PC-12 and HCT-116 cell lines. The potency of activity was observed to be decreased in the order of spirostane, furostane, spirosolane, and pregnane type steroid glycosides. It was also suggested that the activity depend on the kind of oligosaccharide moiety and aglycone moiety.

Animals↗
PubMed2003

Anti-tumor promoting effect of glycosides from Prunus persica seeds.

Four minor components, along with the major cyanogenic glycosides, amygdalin and prunasin, were isolated from Prunus persica seeds (Persicae Semen; Tounin), and characterized as mandelic acid glycosides (beta-gentiobioside and beta-D-glucoside) and benzyl alcohol glycosides (beta-gentiobioside and beta-D-glucoside). The anti-tumor promoting activity of these compounds was examined in both in vitro and in vivo assays. All of the compounds significantly inhibited the Epstein-Barr virus early antigen activation induced by tumor promoter. In addition, they produced a delay of two-stage carcinogenesis on mouse skin that was comparable in potency to (-)-epigallocatechin gallate from green tea. Structure-activity relationships indicated that a substituent at the benzylic position with glycosidic linkage affected the in vitro and in vivo activities with an order of enhancing potency, CN<COOH<H.

Animals↗
PubMed1990

Inhibitory effects of flavonol glycosides on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion.

The two-stage carcinogenesis by 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate (TPA) in mice was inhibited by kaempferol and flavonol glycosides, whereas naringenin, a flavanone, had no effect. The induction of epidermal ornithine decarboxylase activity by TPA was also inhibited by kaempferol, whereas mauritianin, a kaempferol glycoside, failed to inhibit it. In addition, the effect of the flavonol glycosides on cell-mediated immunosuppression in the two-stage carcinogenesis, observed in terms of initiation after 14 weeks, was antagonized by mauritianin and myricitrin. Cell-mediated immunosuppression in the two-stage carcinogenesis was unaffected by kaempferol and naringenin. These results suggest that the inhibitory effects of flavonol glycosides may have been at least partly due to activation of immune responses against tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Permeability of glycosides through human erythrocyte membrane.

The permeability of glycosides (arbutin, salicin, glycyrritin, p-nitrophenyl-beta-D-glucopyranoside, p-nitrophenyl-beta-D-galactopyranoside, p-nitrophenyl-beta-D-lactopyranoside, p-nitrophenyl-beta-D-maltopyranoside) and their aglycons through human erythrocyte membrane was investigated. The glycosides permeated slowly, compared with their aglycons. Glycoside having disaccharide did not permeate the erythrocyte membrane. This suggested that the introduction of disaccharide to a drug significantly depresses the permeability of glycoside through erythrocyte membrane. The drug entrapped in erythrocytes was not released into the outer medium.

Cell Membrane Permeability↗
PubMed1991

Preparation of glycyrrhetic acid glycosides having various beta(1----2)-linked disaccharides and their cytoprotective effects on carbon tetrachloride-induced hepatic injury.

Glycyrrhetic acid glycosides (1-7) having beta(1----2)-linked disaccharides such as 2-O-beta-D-glucopyranosyl-beta-D-galactopyranose, 2-O-beta-D-galactopyranosyl-beta-D-galactopyranose, 2-O-beta-D-glucuronopyranosyl-beta-D-galactopyranose, 2-O-beta-D-glucopyranosyl-beta-D-glucuronopyranose, 2-O-beta-D-galactopyranosyl-beta-D-glucuronopyranose, 2-O-beta-D-galactopyranosyl-beta-D-glucopyranose, 2-O-beta-D-glucuronopyranosyl-beta-D-glucopyranose, respectively, were synthesized by stepwise construction; from glycyrrhetic acid monoglycosides to the diglycosides. The cytoprotective activities of the glycosides 1-7 and 2-O-(beta-D-glucopyranosyl)-beta-D-glucopyranosyl-11-oxoolean-12-e n-30-oate (8) were compared with natural occurring glycyrrhizin (9). Among these glycosides 1-8, glycosides 3 and 7 having beta-D-glucuronopyranose (glcUA) as the only terminal sugar component were more effective materials against hepatic injury than glycyrrhizin 9.

Animals↗
PubMed1993

Cyclic peptides, acyclic diterpene glycosides and other compounds from Lycium chinense Mill.

The chemical structures of four cyclic peptides, lyciumins A-D (1-4), three acyclic diterpene glycosides, lyciumosides I-III (5-7) and other three compounds, a tryptophan derivative glycoside (8), a monoterpene glycoside (9) and a steroidal glycoside (10) isolated from Lycium chinense, have been elucidated by a combination of chemical, 1H- and 13C-NMR, and mass spectrometric studies. Lyciumins are interesting because of their monocyclic octapeptides containing a novel C-N linkage between tryprophan N1 and glycine C alpha.

Amino Acid Sequence↗
PubMed1994

Steroidal glycosides from Asclepias fruticosa L.

Five novel steroidal glycosides 2-6 were isolated from the whole plant of Asclepias fruticosa L. (Asclepiadaceae). The structures of these steroidal glycosides were determined on the basis of spectral and chemical evidence. All of these glycosides contain 2,6-dideoxyhexopyranoses as component sugars and their structures were elucidated as polyoxypregnane-type glycosides, which have lineolon as the aglycone moiety.

Carbohydrate Sequence↗
PubMed1997

Resin glycosides. XXV. Multifidins I and II, new jalapins, from the seed of Quamoclit x multifida.

Alkaline hydrolysis of the ether-soluble resin glycoside fraction of seeds of Quamoclit (Q.) x multifida, a hybrid between Q. pinnata and Q. coccinea, gave new glycosidic acids, multifidinic acids A and B, along with two known glycosidic acids, quamoclinic acid A and operculinic acid A, and three organic acids, (2S)-2-methylbutyric acid, n-decanoic acid and n-dodecanoic acid. Further, as major ether-soluble resin glycosides, new jalapins named multifidins I and II, were isolated accompanied by quamoclins I-IV, which were previously obtained from seeds of Q. pinnata. The structures of multifidins I and II, and multifidinic acids A and B have been determined on the basis of chemical and spectral data.

Butyrates↗