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PubMedDate not supplied

Current status of cardiac glycoside drug interactions.

The effects of concomitant drug therapy on the absorption, distribution, and elimination of digoxin and digitoxin are reviewed. A number of agents can increase or decrease the absorption of digoxin and digitoxin from the gastrointestinal tract by altering GI motility, binding the drugs through physical adsorption, altering the properties of the intestinal wall, or altering the bacterial flora of the intestine. The steady-state serum concentrations of digoxin and digitoxin can be affected if the changes in absorption are of sufficient magnitude, and adjustments in digoxin or digitoxin dosage may be required. A reduction in digoxin and digitoxin protein binding has occurred during concomitant administration of heparin and cardiac glycosides. Since digitoxin is more highly protein bound than digoxin, interactions that involve changes in protein binding are of much greater clinical importance with digitoxin. A number of drugs increase or decrease the elimination of digoxin and digitoxin, and subtherapeutic or toxic concentrations of the cardiac glycosides often result. Drugs that induce hepatic microsomal enzymes can increase the elimination of digitoxin, which is eliminated mainly by hepatic biotransformation. Digoxin is eliminated mainly by renal excretion; renal clearance of digoxin may be increased by vasodilators and thyroid hormones and decreased by quinidine, verapamil, amiodarone, and potassium-sparing diuretics. The clinical importance of changes in serum concentrations of the cardiac glycosides that result from alterations in glycoside elimination requires further study, as does the importance of preliminary reports of interactions between cardiac glycosides and diazepam, captopril, and combination therapy with quinidine-pentobarbital or quinidine-rifampin. Because the cardiac glycosides have a narrow therapeutic range, patients receiving concomitant therapy with agents that might affect the absorption, distribution, or elimination of the cardiac glycosides should be monitored carefully for symptoms of digitalis toxicity or undertreatment.

Anti-Arrhythmia Agents↗

PubMed1985

Cross-resistance and biochemical studies with two classes of HeLa cell mutants resistant to cardiac glycosides. The unusual behavior of cardenolide SC4453.

In HeLa cells two different types of mutants resistant to the cardiac glycoside ouabain (OuaR mutants) or erythrophleum alkaloid cassaine (CasR mutants) have been obtained. One type of mutants resistant to these compounds (designated as group A) are highly resistant (between 50 and 2000-fold) to various cardiac glycosides and their genins such as ouabain, oleandrin, digitoxin, digitoxigenin, strophanthidin, convallatoxin, gitoxin, gitoxigenin, gitaloxin, bufalin, and digoxigenin, but exhibit no cross-resistance to SC4453, a digoxin analog which contains a pyridazine ring in place of the lactone ring in the C-17 position. The second type of mutants (group B) exhibit cross-resistance to all of the cardiac glycosides including SC4453, but their level of resistance is at least 5-10-fold less than that of group A mutants. Interestingly, both groups of mutants exhibited similar degree of cross-resistance towards digoxin and actodigin (AY22241), indicating some differences in their behavior from other cardiac glycosides. Both classes of mutants exhibit no cross-resistance to a wide variety of other structurally and functionally related compounds, e.g. sanguinarine nitrate, ethacrynic acid, penicillic acid, veratridine, harmaline hydrochloride, 5,5'-diphenylhydantoin, quindonium bromide, methyl quinolizinum bromide, estradiol 17 beta-acetate, 21-acetoxy-pregnenolone, vanadium pentoxide, digitonin, and adriamycin, indicating that the genetic lesions in both groups of mutants are specific for cardiac glycosides. This inference is supported by the observation that both group A and B mutants show reduced binding of [3H]ouabain. In group A mutants, a part of the Na+/K+-ATPase activity is highly resistant to inhibition by ouabain, indicating that the genetic lesion in these mutants directly affects Na+/K+-ATPase. In contrast, the Na+/K+-ATPase from the group B mutants showed similar resistance towards ouabain and SC4453 as observed for the parental HeLa cells, indicating that these mutants are affected in a cellular component, other than Na+/K+-ATPase, which is involved in the interaction of cardiac glycosides with the cells. The lack of cross-resistance of the group A mutants to SC4453 and normal sensitivity of their Na+/K+-ATPase to this compound provides strong evidence that the mechanism of interaction of SC4453 with Na+/K+-ATPase differs from that of other cardiac glycosides.

Abietanes↗

PubMed1985

[Age-dependent regulation of cardiac glycoside receptors].

Specific binding of cardiac glycosides to their receptors precedes their actions on the myocardium. Thus changes in the number and affinity of these membrane bound receptors will vary the response to cardiac glycoside therapy and the incidence of side-effects. Several studies have reported an age-dependent decrease in the number of cardiac glycoside receptors in animals as well as in human erythrocytes. These results may explain the increase in cardiac glycoside sensitivity with age which is not accounted for by the reduction in kidney function. Furthermore, changes in both binding affinity and capacity are known to occur in several diseases which are more common in older patients. Therefore, we have measured the number and affinity of cardiac glycoside receptors in atrial samples from 209 patients and in papillary muscle samples from 59 patients taken during coronary bypass graft surgery or mitral valve replacement. Further, the maximal increase in force of contraction was measured using papillary muscle strips from some of these patients. Our results show no significant age-dependent alteration in the characteristics of the cardiac glycoside receptors but a reduced myocardial receptor density in males (3.47 +/- 0.14 X 10(14)/g protein) compared with females (4.44 +/- 0.21 X 10(14)/g protein) (p less than 0.001) which is more pronounced in older patients. About 30% fewer cardiac receptors either per g protein or per g wet weight are present in patients with coronary heart disease or dilative cardiomyopathy. The maximal inotropic effect of ouabain in human papillary muscle strips is correlated with the number of cardiac glycoside receptors present.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2000

Transgalactosylation by thermostable beta-glycosidases from Pyrococcus furiosus and Sulfolobus solfataricus. Binding interactions of nucleophiles with the galactosylated enzyme intermediate make major contributions to the formation of new beta-glycosides during lactose conversion.

The hyperthermostable beta-glycosidases from the Archaea Sulfolobus solfataricus (SsbetaGly) and Pyrococcus furiosus (CelB) hydrolyse beta-glycosides of D-glucose or D-galactose with relaxed specificities pertaining to the nature of the leaving group and the glycosidic linkage. To determine how specificity is manifested under conditions of kinetically controlled transgalactosylation, the major transfer products formed during the hydrolysis of lactose by these enzymes have been identified, and their appearance and degradation have been determined in dependence of the degree of substrate conversion. CelB and SsbetaGly show a marked preference for making new beta(1-->3) and beta(1-->6) glycosidic bonds by intermolecular as well as intramolecular transfer reactions. The intramolecular galactosyl transfer of CelB, relative to glycosidic-bond cleavage and release of glucose, is about 2.2 times that of SsbetaGly and yields beta-D-Galp-(1-->6)-D-Glc and beta-D-Galp-(1-->3)-D-Glc in a molar ratio of approximately 1 : 2. The partitioning of galactosylated SsbetaGly between reaction with sugars [kNu (M-1. s-1)] and reaction with water [kwater (s-1)] is about twice that of CelB. It gives a mixture of linear beta-D-glycosides, chiefly trisaccharides at early reaction times, in which the prevailing new glycosidic bonds are beta(1-->6) and beta(1-->3) for the reactions catalysed by SsbetaGly and CelB, respectively. The accumulation of beta-D-Galp-(1-->6)-D-Glc at the end of lactose hydrolysis reflects a 3-10-fold specificity of both enzymes for the hydrolysis of beta(1-->3) over beta(1-->6) linked glucosides. Galactosyl transfer from SsbetaGly or CelB to D-glucose occurs with partitioning ratios, kNu/kwater, which are seven and > 170 times those for the reactions of the galactosylated enzymes with 1-propanol and 2-propanol, respectively. Therefore, the binding interactions with nucleophiles contribute chiefly to formation of new beta-glycosides during lactose conversion. Likewise, noncovalent interactions with the glucose leaving group govern the catalytic efficiencies for the hydrolysis of lactose by both enzymes. They are almost fully expressed in the rate-limiting first-order rate constant for the galactosyl transfer from the substrate to the enzyme and lead to a positive deviation by approximately 2.5 log10 units from structure-reactivity correlations based on the pKa of the leaving group.

Carbohydrate Sequence↗

PubMed2002

Evidence for lack of absorption of soy isoflavone glycosides in humans, supporting the crucial role of intestinal metabolism for bioavailability.

BACKGROUND: The isoflavones daidzein and genistein occur naturally in most soyfoods, conjugated almost exclusively to sugars. Controversy exists regarding the extent of bioavailability of isoflavone glycosides, and the mechanism of intestinal absorption of isoflavones in humans is unclear. Evidence from intestinal perfusion and in vitro cell culture studies indicates that isoflavone glycosides are poorly absorbed, yet isoflavones are bioavailable and appear in high concentrations in plasma, irrespective of whether they are ingested as aglycones or glycoside conjugates. OBJECTIVE: The objective was to determine whether isoflavone glycosides are absorbed from the intestine intact and reach the peripheral circulation unchanged. DESIGN: Plasma was collected at timed intervals before and after healthy adults ingested 50 mg of one of the isoflavone beta-glycosides (daidzin or genistin) or 250 mL soymilk containing mainly isoflavone glycosides. Electrospray ionization mass spectrometry was used to detect daidzin and genistin after solid-phase extraction of these conjugates from plasma. Bioavailability of isoflavones was confirmed by gas chromatography-mass spectrometry analysis. RESULTS: Specific and sensitive electrospray mass spectrometry failed to detect even traces of daidzin or genistin in plasma collected 1, 2, and 8 h after their ingestion as pure compounds or in a soyfood matrix. However, plasma was enriched in isoflavones that were hydrolyzable with a combined beta-glucuronidase and sulfatase enzyme preparation. CONCLUSION: Isoflavone glycosides are not absorbed intact across the enterocyte of healthy adults, and their bioavailability requires initial hydrolysis of the sugar moiety by intestinal beta-glucosidases for uptake to the peripheral circulation.

Adult↗

PubMed1974

Steryl Glycoside Formation in Seedlings of Nicotiana tabacum L.

Particulate enzyme preparations from tobacco seedlings (Nicotiana tabacum L.) were used in the synthesis of steryl glycoside. The data obtained by measuring cholesterol-4-(14)C incorporation generally agree with results obtained with UDP-glucose-(14)C. The in vitro reaction was linear for the first 10 minutes and had a pH optimum of 7.0 to 7.4. Addition of ATP activated while UDP-glucose inhibited slightly the reaction. In short term experiments, the percentage disappearance of endogenous and added sterol was about the same.Intact tobacco seedlings incorporated cholesterol-4-(14)C and sitosterol-4-(14)C into their steryl glycosides. The acylated steryl glycosides were more rapidly labeled than the nonacylated form. After 12 hours of incubation with cholesterol-4-(14)C, about 5% of the radioactivity was recovered as steryl glycoside and 12% as acylated steryl glycoside. Incubation for 12 hours with authentic cholesteryl-(14)C glucoside gave only a 4% acylation, and under these conditions 21% of the radioactivity was recovered as free cholesterol. It is suggested that acylated steryl glycosides may be formed through the acylation of steryl glycosides or the transfer of an acyl-glycosyl group to sterol.

Journal Article↗

PubMed1980

Inhibition of steryl glycoside biosynthesis by acyl coenzyme a and by digitonin.

ATP, GTP, CoA, Mg(2+), and Mn(2+) did not inhibit biosynthesis of steryl glycoside and acylated steryl glycoside when added singly to enzyme preparations from spinach leaves. The combination of ATP (but not GTP), CoA, and Mg(2+) or Mn(2+) caused marked inhibition, especially of steryl glycoside biosynthesis, when reaction mixture concentrations of the additions were 0.2 millimolar. Inhibition was attributed to acyl-CoA and could be reproduced by palmitoyl-CoA. The inhibition could be partially prevented by bovine serum albumin. The effects of palmitoyl-CoA were distinct at 10 micromolar, and 50% inhibition of biosynthesis was observed at 40 micromolar.Digitonin (0.6 millimolar) stopped steryl glycoside biosynthesis but permitted the conversion of steryl glycoside to acylated steryl glycoside, thus eliminating the possibility that acylated steryl glycoside is formed from sterol + an acyl-glucose donor.

Journal Article↗

PubMed1998

Induction of KDNase Sm, a deaminoneuraminic acid (KDN) residue-specific sialidase from Sphingobacterium multivorum, using synthetic KDN-glycosides.

Various aryl and alkyl alpha-glycosides of KDN were synthesized and tested as substrates for their susceptibility to a deaminoneuraminic acid (KDN)-specific sialidase from Sphingobacterium multivorum, designated KDNase Sm. The synthetic KDN-glycosides were all hydrolyzed by the action of KDNase Sm. A hydroxyl group at C-5 position of KDN was required for the recognition by the enzyme, and was shown not to be replaced by an amino- or an acylamino group for the enzymatic recognition. These synthetic KDN-glycosides were also examined for their inducing activity of KDNase in S. multivorum and were shown to induce the KDNase activity effectively when the bacterium was cultured minimum salt medium containing both 0.1% glucose and 0.1% various KDN-glycosides. No KDNase activity was induced by the KDN-glycosides without 0.1% glucose. This is the first case of using synthetic KDN-glycosides as inducers of KDNase Sm.

Carbohydrate Conformation↗

PubMed1980

Fecalase: a model for activation of dietary glycosides to mutagens by intestinal flora.

Many substances in the plant kingdom and in man's diet occur as glycosides. Recent studies have indicated that many glycosides that are not mutagenic in tests such as the Salmonella test become mutagenic upon hydrolysis of the glycosidic linkages. The Salmonella test utilizes a liver homogenate to approximate mammalian metabolism but does not provide a source of the enzymes present in intestinal bacterial flora that hydrolyze the wide variety of glycosides present in nature. We describe a stable cell-free extract of human feces, fecalase, which is shown to contain various glycosidases that allow the in vitro activation of many natural glycosides to mutagens in the Salmonella/liver homogenate test. Many beverages, such as red wine (but apparently not white wine) and tea, contain glycosides of the mutagne quercetin. Red wine, red grape juice, and tea were mutagenic in the test when fecalase was added, and red wine contained considerable direct mutagenic activity in the absence of fecalase. The implications of quercetin mutagenicity and carcinogenicity are discussed.

Adult↗

PubMed1972

Species and ionic influences on the accumulation of digitalis glycosides by isolated perfused hearts.

1. The ability of isolated perfused guinea-pig (digitalis-sensitive species) and rat (digitalis-resistant species) hearts to accumulate radio-labelled digitalis glycosides was studied in relation to the ionic composition of the perfusion medium.2. It was observed that in both species much less digoxin was accumulated than was digitoxin or proscillaridin.3. The accumulation of digoxin was markedly inhibited in a low sodium or in high potassium medium. These effects were similar, but relatively less marked, with digitoxin and proscillaridin. Calcium and magnesium removal had relatively smaller effects on the accumulation of both polar and non-polar glycosides.4. The low accumulation of all digitaloids by the rat heart in comparison to the guinea-pig heart may be due to the formation of unstable complexes between the cellular membranes in the rat heart and the various digitaloids used in this study. Although digitaloids have a reduced affinity for rat hearts and rat heart membranes in comparison to guinea-pigs, the order of the accumulation of different glycosides in both species is the same, i.e. much less with polar glycosides than with non-polar glycosides.5. It was concluded that non-polar glycosides such as digitoxin and proscillaridin demonstrate the same ion-dependent accumulation mechanism as do the more polar glycosides such as digoxin and ouabain. In addition, the non-polar glycosides possess high capacity for ion-independent binding presumably due to lipophilic interactions with membranes.

Animals↗

PubMed1991

4-Trifluoromethylumbelliferyl glycosides as new substrates for revealing diseases connected with hereditary deficiency of lysosome glycosidases.

The following glycosides of 4-trifluoromethylumbelliferone: alpha-D-mannopyranoside, alpha-L-fucopyranoside, alpha-D-glucopyranoside, beta-D-glucopyranoside, alpha-D-galactopyranoside, beta-D-galactopyranoside, alpha-L-iduronide and beta-D-glucuronide were studied. 4-Trifluoromethylumbelliferyl glycosides were shown to be substrates for glycosidases. Some of them were cleaved even better than the corresponding methylumbelliferyl glycosides. 4-Trifluoromethylumbelliferyl glycosides were applied for revealing the corresponding enzyme deficiencies upon diagnosis of Gaucher and Hurler diseases as well as GM1 gangliosidosis and alpha-mannosidosis. 4-Trifluoromethylumbelliferone released after enzymatic hydrolysis of 4-trifluoromethylumbelliferyl glycosides exhibits more contrast yellow fluorescence in UV-light than the blue one of methylumbelliferone upon exposure of enzyme activity on solid supports. Therefore 4-trifluoromethylumbelliferyl glycosides are convenient substrates for revealing glycosidase activity directly in tissue samples, e.g. in placenta, and thus for fast prenatal diagnosis of lysosomal diseases.

Clinical Enzyme Tests↗

PubMed1998

Influence of different glycosidic linkages on relative ion intensities in post-source decay fragmentation of a xyloglucan heptaoligosaccharide using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Post-source decay fragment analysis using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) has been applied to a highly branched xyloglucan heptasaccharide from tamarind seed. All fragment ions were produced by cleavage of the glycosidic linkages, including multi-site cleavages. The relative intensities of fragment ions that originated from one-site cleavages of the glycosidic linkages were much higher than those arising from two-site cleavages of the same kind of glycosidic linkage, which were in turn higher than those from three-site cleavages. The types of glycosidic linkages were an important factor which influenced the relative intensities of the MALDI-PSD (post-source decay) fragment ions. In the MALDI-PSD fragment spectrum of the xyloglucan heptasaccharide, the relative intensities of the ions produced by the cleavage of an alpha 1-6 glycosidic linkage were much higher than those arising from cleavage of the beta 1-4 glycosidic linkage.

Carbohydrate Sequence↗

PubMed2005

Determination of the glycosylation site in flavonoid mono-O-glycosides by collision-induced dissociation of electrospray-generated deprotonated and sodiated molecules.

The influence of the glycosylation site on the fragmentation behavior of 18 flavonoid glycoside standards was studied using positive and negative electrospray ionization mass spectrometry in combination with collision-induced dissociation and tandem mass spectrometry. The glycosylation position is shown to affect the relative abundance of the radical aglycone ions that can be observed in the [M-H]- collision-induced dissociation spectra. In particular, the radical aglycone ions are very abundant for deprotonated flavonol 3-O-glycosides. Collisional activation of the radical aglycone ions produced from positional isomers revealed minor differences: m,nB0- product ions are pronounced for 7-O-glycosides, whereas m,nA0- product ions are relatively more abundant for 4'-O-glycosides. In addition, the ratio between the radical aglycone and the regular aglycone ions in the [M+Na]+ high-energy collision-induced dissociation spectra gives an indication about the glycosylation site. This ion ratio allows the differentiation between flavonoid 3-O- and 7-O-glycosides or can be useful in the comparison of unknown compounds with standards. Unambiguous differentiation between O-glycosylation at the common positions of flavonoid O-glycosides, i.e. the 3-, 4'- and 7-positions, is achieved by collisional activation of sodiated molecules at high collision energy. The presence of a B-ring product ion containing the sugar residue indicates 4'-O-glycosylation, whereas the loss of the B-ring part from the aglycone product ion is characteristic of 3-O-glycosylation and the loss of the B-ring part from both the [M+Na]+ precursor ion and the aglycone product ion points to 7-O-glycosylation.

Flavonoids↗

PubMed2002

A direct continuous spectrophotometric assay for glycosidases with 3-nitro-2-pyridyl glycosides by tautomerization of 2-hydroxy-3-nitropyridine.

Two kinds of 3-nitro-2-pyridyl glycosides were synthesized and evaluated as substrates for continuous spectrophotometric assay for glycosidases. The liberated aglycon, 2-hydroxy-3-nitropyridine, immediately tautomerized to 3-nitro-2(1H)-pyridone, causing an absorption shift of ca. 60 nm even under acidic conditions (pH 3-6). Consequently, the enzymatic hydrolysis of these glycosides was monitored continuously in the acidic to neutral pH range (pH 4-7), the optimum pH for most glycosidases. The absorbance of liberated aglycon increased linearly at 390 nm until 10% consumption of the substrate to enable the initial rate to be determined at once without terminating the reaction. The kinetic parameters for the hydrolysis of 3-nitro-2-pyridyl glycosides were obtained from the slopes of the progress curves and were compared with those obtained from the conventional discontinuous assay using p- and o-nitrophenyl glycosides as substrates. The kinetic parameters indicated that 3-nitro-2-pyridyl glycosides were more activated and specific substrates, but with less affinity to the enzymes than the corresponding nitrophenyl glycosides. Moreover, the absorbance shift by tautomerization should promise further applications to continuous spectrophotometric assays for other enzymes acting under acidic conditions, such as acid proteases and acid phosphatases.

Aspergillus niger↗

PubMed1981

[The problem of the cellular receptor for cardiac glycosides (author's transl)].

This review concerns the Na+, K+ -ATPase as well as the Na+, K+ -pump in the intact membrane and the highly specific inhibition of this transport system by cardiac glycosides. The interaction between glycoside and enzyme and the regulation of the kinetics of glycoside binding by ATP, K+, Na+, Mg2+ and Ca2+ are described. Emphasis is placed on the significance of the Na+, K+ -pump as the pharmacological receptor for cardiac glycosides. The problem encountered and progress made in attempting to correlate the inotropic action of cardiac glycosides with the binding of these drugs to the heart muscle and with the inhibition of the Na+, K+ -pump are reported. Recent results concerning increases of the intracellular Na+ concentration which are obtained by a partial inhibition of the Na+, K+ -pump and which are followed by an elevation of the intracellular Ca2+ -activity are reviewed. The discovery of a digitalis-like endogenous activity corresponds to the high specificity of the receptor for cardiac glycosides.

Cardiac Glycosides↗

PubMed2003

Deglycosylation by small intestinal epithelial cell beta-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans.

BACKGROUND: Pharmacokinetic studies have shown that the small intestine is the major site of absorption for many flavonoid glucosides. Flavonoids are generally present as glycosylated forms in plants and foods, but there is increasing evidence that the forms reaching the systemic circulation are glucuronidated, sulphated and methylated derivatives. Hence, first-pass metabolism (small intestine-liver) appears to involve a critical deglycosylation step for which the mechanisms are not known. AIMS: To explore the hypothesis that deglycosylation is a prerequisite to absorption and metabolism of dietary flavonoid glycosides, to identify the enzymes responsible, and relate their specificities with absorption kinetics. METHODS: Flavonoid glycoside hydrolysing enzymes were isolated from samples of human small intestine and liver using chromatographic techniques. The proteins were characterised with respect to the cellular fraction with which they were associated, molecular weight, specificity for various substrates, and cross-reactions with antibodies. Cellular models were used to mimic the small intestine. RESULTS: Protein extracts from human jejunal mucosa were highly efficient in hydrolysing flavonoid glycosides, consistent with an enterocyte-mediated deglycosylation process. Considerable inter-individual variation was observed [e. g. range, mean and standard deviation for rate of hydrolysis of quercetin-3-glucoside (n = 10) were 6.7-456, 96, and 134 nmol min(-1) (mg protein)(-1), respectively]. Two beta-glucosidases with activity towards flavonoid glycosides were isolated from human small intestine mucosa: lactase-phlorizin hydrolase (LPH; localised to the apical membrane of small intestinal epithelial cells) and cytosolic beta-glucosidase (CBG), indicating a role of human LPH and CBG from small intestine in flavonoid absorption and metabolism. Hydrolysis of flavonoid glycosides was only detected in cultured cells exhibiting beta-glucosidase activity. CONCLUSIONS: The absorption of dietary flavonoid glycosides in humans involves a critical deglycosylation step that is mediated by epithelial beta-glucosidases (LPH and CBG). The significant variation in beta-glucosidase activity between individuals may be a factor determining variation in flavonoid bioavailability.

Antibodies, Monoclonal↗

PubMed1992

A multispecific uptake system for taurocholate, cardiac glycosides and cationic drugs in the liver.

To test the hypothesis of multiplicity in carrier-mediated uptake mechanisms for organic cations in the liver and to study the possible relation with bile acid and cardiac glycoside uptake mechanisms, mutual interaction during uptake of various radiolabeled quaternary amines has been studied in isolated rat hepatocytes. Inhibition patterns at low concentrations (1 microM) of the presumed type I monovalent organic cation tri-n-butylmethylammonium were markedly different from those at relatively high concentrations (25 microM). Both the cardiac glycoside K-strophantoside and the bile acid taurocholate clearly reduced the uptake rate of tri-n-butylmethylammonium at 25 microM whereas these agents completely failed to reduce the uptake at low concentrations of the cation. Subsequently, inhibition of uptake of some multivalent amphipathic organic cations (muscle relaxants) for the type II uptake system was investigated. It was found that the uptake of these muscle relaxants both at tracer concentrations (< 1 microM) and at relatively high concentrations (25 microM) was decreased in the presence of low concentrations of the cardiac glycoside K-strophantoside, while taurocholate only inhibited the uptake at the concentration range > 25 microM of the muscle relaxants. Procainamide ethobromide, a typical type I organic cation, did not affect the uptake either at the low or high concentration range of the muscle relaxants. It is concluded that for each of the type I-like compounds and type II-like compounds tested at least two systems are involved in uptake into hepatocytes: tri-n-butylmethylammonium in a concentration range < or = 1 microM is mainly taken up by the type I uptake system and at concentrations > or = 25 microM also by system(s) that can be inhibited by taurocholate and K-strophantoside. Bulky amphipathic organic (type II) cations at concentrations < 1 microM are also transported by an uptake system that is inhibitable by cardiac glycosides but not by bile salts. At concentrations > 25 microM these compounds are predominantly accommodated by an uptake system that possibly mediates uptake of both cardiac glycosides and bile acids. This concept was supported by the observation that both type II organic cations and bile salts can inhibit ouabain uptake, while type II organic cations as well as the cardiac glycosides reduce taurocholate uptake rate. The present data support the idea that the liver seems to be equipped with a "multispecific" uptake system that transports hydrophobic compounds irrespective of charge, including some type I and type II organic cations at relatively high substrate concentrations.

Androstanols↗

PubMed1990

Multiple and long-range participation of benzyl groups in intramolecular C-arylation reactions of benzylated glycosides.

The intrinsic reactivity of furanosides bearing activated O-benzyl substituents (3-methoxybenzyl), in the presence of bidentate Lewis acids such as tin(IV) chloride, was explored. These glycosides were found to exhibit extremely interesting chemical properties. Thus, with three reactive substituents (at O-2,3,5), the corresponding glycosides (1 and 7) underwent a novel internal bis-C-arylation process, which involved successive alkylations of the benzyl groups at O-2 and O-3 ("multiple participation"), leading to the formal replacement of the two C-O bonds at the anomeric center of the glycoside by two C-C bonds. The bis-C-arylated constitution of the resulting polycyclic compounds 4 and 8, and the cis configuration of their fused ring system (a tetrahydro-[2]benzopyrano[3,4-d][2]benzoxepin derivative), were determined on the basis of their n.m.r.-spectral parameters. With two 3-methoxybenzyl substituents (at O-3 and O-5, compound 6), intramolecular alkylation of the benzyl group at O-3 or O-5 occurred when glycoside 6 was reacted with titanium(IV) chloride or tin(IV) chloride, respectively, thereby leading to novel bicyclic internal aryl C-glycosides (9 and 12) as major products ("long-range participation"). The constitution of compounds 9 and 12 was unambiguously established by the reactions of analogs of 6 bearing only one 3-methoxybenzyl substituent at a specific position (at O-3: 15; at O-5: 20). The unexpected divergent behavior of 6 in the presence of titanium(IV) and tin(IV) chloride remains to be explained. The availability of compound 9 made it possible to independently prepare the bis-C-arylated derivative 8 (by way of the reverse sequence of internal C-arylation reactions) and thereby to definitively demonstrate its constitution. These unprecedented reactions extend the scope of the intramolecular C-glycosidation of substituted sugars and provide novel methodologies in synthetic carbohydrate chemistry.

Benzyl Compounds↗