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PubMed1981

Inorganic cation transport and the effects on C4 dicarboxylate transport in Bacillus subtilis.

The complex interrelationships between the transport of inorganic cations and C4 dicarboxylate were examined using mutants defective in potassium transport and retention, divalent cation transport, or phosphate transport. The potassium transport system, studied using 86Rb+ as a K+ analogue, kinetically appeared as a single system (Km 200 microM for Rb+, Ki 50 microM for K+), the activity of which was only slightly reduced in K+ retention mutants. Divalent cation transport, studied using 54Mn2+, 60Co2+, and 45Ca2+, was more complex being represented by at least two systems, one with a high affinity for Mn2+ (Km 2.5 microM) and a more general one of low affinity (Km 1.3-10 mM) for Mg2+, Mn2+, Ca/2+, and Co2+. Divalent cation transport was repressed by Mg2+, derepressed in K+ retention mutants, and defective in Co2+-resistant mutants. Phosphate was required for both divalent cation and succinate transport, and phosphate transport mutants (arsenate resistant) were found to be defective in both divalent cation and succinate transport. Divalent cations, especially Mg2+ and Co2+, decreased Km for succinate transport approximately 20-fold over that achieved with K+; neither cation was required stoichiometrically for succinate transport. The loss of divalent cation transport in cobalt-resistant mutants has been correlated with the loss of a 55,000 molecular weight membrane protein. Similarly, the loss of phosphate transport in arsenate-resistant mutants has been correlated with the loss of a 35,000 molecular weight membrane component.

Bacillus subtilis↗
PubMed1992

Organic cation transport by rat liver plasma membrane vesicles: studies with tetraethylammonium.

Recently, an organic cation:H+ antiport was selectively identified on the sinusoidal domain of rat liver with the use of the endogenous organic cation N1-methylnicotinamide (NMN). Absence of NMN+:H+ exchange on canalicular membrane suggested that this transport process was primarily involved in organic cation uptake, leaving the mechanism(s) for organic cation secretion into bile unknown. To further define hepatic organic cation transport, we examined the characteristics of tetraethylammonium (TEA) transport in basolateral (blLPM) and canalicular (cLPM) rat liver plasma membrane vesicles. In cLPM vesicles, under voltage-clamped conditions, an outwardly directed H+ gradient stimulated [14C]TEA uptake compared with [14C]TEA uptake under pH-equilibrated conditions, consistent with electroneutral TEA:H+ exchange. The proton ionophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone had no effect on [14C]TEA uptake, demonstrating that pH-dependent [14C]TEA uptake was not the result of a H+ diffusion potential. In the absence of a pH gradient, the intravesicular presence of TEA trans-stimulated uptake of [14C]TEA. Procainamide ethobromide (PAEB), vecuronium, and tributylmethylammonium (TBuMA), organic cations selectively excreted in bile, cis-inhibited pH-dependent TEA uptake. In contrast, in blLPM vesicles, no pH gradient-dependent [14C]TEA uptake was demonstrated. Instead, basolateral [14C]TEA uptake was significantly stimulated by a valinomycin-induced intravesicular-negative K+ diffusion potential. Basolateral [14C]TEA uptake was also cis-inhibited by PAEB, vecuronium, and TBuMA, but not by NMN. Conversely, PAEB, vecuronium, and TBuMA had no effect on basolateral pH-dependent [3H]NMN uptake. These findings suggest that organic cation transport, with TEA as a model quaternary amine, across the canalicular membrane is driven by an electroneutral organic cation:H+ exchange and that the transport of certain organic cations across the basolateral membrane is via a carrier-mediated system stimulated by an inside-negative membrane potential.

Animals↗
PubMed1997

Gene transfection by cationic liposomes: comparison of the transfection efficiency of liposomes prepared from various positively charged lipids.

We compared the transfection efficiency of four types of positively charged liposomes composed of (i) N-(alpha-trimethylammonioacetyl)-didodecyl-D-glutamate chloride (TMAG), dilauroylphosphatidylcholine (DLPC), and dioleoylphosphatidylethanolamine (DOPE) (1:2:2 molar ratio); (ii) 3 beta [N-(N', N'-dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol) and DOPE (3:2 molar ratio); (iii) dimethyldioctadecylammonium bromide (DDAB) and DOPE (1:2.2 molar ratio); (iv) N-[1-(2,3-dioleyloxy) propyl]-N,N,N-trimethylammonium chloride (DOTMA) and DOPE (1:1, w/w; lipofectin). Luciferase gene was used as a reporter gene. Among the cationic lipsomes used, the liposomes composed of TMAG, DOPE and DLPC showed a much higher efficiency of plasmid DNA entrapment than the other cationic liposomes tested. In the absence of serum, the cationic multilamellar vesicles (MLV) and small unilamellar vesicles (SUV) composed of TMAG, DOPE and DLPC gave highly efficient transfection. On the other hand, MLV, dehydration-rehydration vesicles (DRV), and SUV liposomes prepared with the mixtures of DC-Chol and DOPE showed similar levels of transfection efficiency. However, the cationic liposomes composed of DDAB and DOPE showed inferior efficiency, whether in the form of DRV, SUV or MLV. The transfection efficiency of lipofectin was also low. In the presence of serum, on the other hand, a considerable (about 30-50%) amount of transfection activity was still observed at 10% fetal calf serum in the cationic MLV and SUV composed of TMAG, DOPE and DLPC. Cationic MLV, composed of TMAG, DOPE and DLPC, Cationic MLV, composed of TMAG, DOPE and DLPC, can transfect plasmid DNA, not only in the adherent cell lines but also, in the suspension cell lines. These findings indicate that the transfection efficiency of cationic liposomes is affected by the lipid composition, the type of liposome, or the presence or absence of serum. They also indicate that the cationic liposomes containing TMAG, DOPE and DLPC are efficient vectors for gene transfer into cells.

Animals↗
PubMedDate not supplied

Cationic proteins increase the permeability of cultured rabbit tracheal epithelial cells: modification by heparin and extracellular calcium.

Airway inflammation is a consistent finding in asthma, and increased amounts of eosinophil-derived cationic proteins are present in bronchoalveolar lavage fluid from asthmatic subjects. Tracheal instillation of a variety of naturally occurring and synthetic cationic proteins has been shown to induce airway hyperresponsiveness in animal models. Cationic proteins may alter the barrier function of airway epithelium, allowing increased access of agonists to underlying nerves and airway smooth muscle. To examine the effect of cationic proteins on airway epithelial cell function, rabbit tracheal epithelial cells were isolated and cultured on collagen-coated filter membranes. Both apical and basolateral exposure of the cell cultures to poly-L-lysine and poly-L-arginine decreased transepithelial electrical resistance (Rt) over 60 min. There were no discernable light microscopic changes in the morphology of the cultures at 60 min after poly-L-lysine exposure, but permeability to mannitol was increased compared to controls. Evidence for the critical role of cationic charge included the following observations: (1) Poly-L-aspartate, an anionic polyamino acid, had no significant effect on Rt, and (2) the addition of heparin prior to the addition of poly-L-lysine blocked the reduction in Rt. Furthermore, when applied after poly-L-lysine addition, heparin reversed the decrease in Rt in a time-dependent fashion. Increasing the [Ca2+] in the medium from 1 to 10 mM resulted in significant attenuation of the response to polycation addition. These findings suggest that cationic proteins significantly alter the barrier properties of airway epithelium and that cationic charge is a crucial factor. This alteration is not an "all or none" phenomenon, since subsequent addition of heparin resulted in a reversal of the effect. While the precise mechanisms responsible for these observations remain to be elucidated, cationic proteins may be modifying the interaction of extracellular calcium with tight junctions thereby resulting in increased permeability. The barrier function of the epithelium may be perturbed in asthma and a variety of other airway diseases through the presence of cationic proteins derived from inflammatory cells within the airway lumen and/or the subepithelium.

Animals↗
PubMed2001

The effect of cation-anion difference on calcium requirement, feed intake, body weight gain, and blood gasses and mineral concentrations of dairy calves.

Our objective was to examine the effects of two diets with different cation-anion differences on Ca requirements in the growing calf. Holstein calves (n = 48, 24 males) were blocked at 56 to 70 d after birth (80+/-10 kg of body weight) according to sex and birth date and assigned randomly in a 2 x 3 factorial arrangement of dietary treatments containing cation-anion differences as meq (Na + K) - (Cl + S)/kg of diet dry matter and Ca content of 1) 0 and 0.35%, 2) 0 and 0.50%, 3) 0 and 0.65%, 4) 200 and 0.35%, 5) 200 and 0.50%, and 6) 200 and 0.65%. Feed intake and average daily gain did not differ among treatment groups. Plasma pH and Ca were unaffected by dietary Ca content or dietary cation-anion difference. Plasma Cl and P decreased linearly with increasing Ca content in the diet. Plasma HCO3 increased linearly with increased dietary Ca content. Plasma HCO3 and partial pressure of CO2 were higher in calves fed the 200 compared with calves fed the 0 cation-anion difference diets. Plasma Cl was, however, lower in calves fed the 200 compared with calves fed the 0 meq diets. An interaction of Ca content and dietary cation-anion difference was detected for plasma P content. Urinary pH increased linearly with increasing dietary Ca content. Calves fed the 200 meq dietary cation-anion difference had higher urinary pH values than those fed the 0 meq diet. Urinary P excretion was not altered by dietary cation-anion difference or Ca content of the diet. Calves fed the 0 meq diet had higher urinary cocnentrations of Ca and Cl when compared with those fed the 200 meq diet. Bone ash, P, Ca, Mg, and K content of the 10th rib were not affected by dietary treatments. Breaking strength of the seventh and ninth ribs increased quadratically with increasing dietary Ca content. Dietary cation-anion difference had no effect on the breaking strength of the seventh and ninth ribs. Varying the dietary cation-anion difference from 0 to 200 meq/kg of dietary dry matter had no effect on Ca requirement of the growing calf.

Animals↗
PubMed1995

Dietary cation-anion difference, acid-base status, mineral metabolism, renal function, and milk production of lactating cows.

Three switchback experiments were conducted with 12 cows in early lactation, 12 cows in midlactation, and 12 cows in late lactation. Each experiment compared two dietary cation-anion differences. Increasing dietary cation-anion difference increased DMI and milk production in early and midlactation. These effects were not observed in late lactation. Production of milk protein and lactose and concentration of lactose were increased by the higher dietary cation-anion difference in early lactation. Higher dietary cation-anion difference reduced milk fat concentration in midlactation because of the higher milk production. In late lactation, none of the milk components were affected by dietary cation-anion difference. In early and midlactation, apparent absorption of water and urine volume were increased by a higher dietary cation-anion difference; these effects were not caused by higher intake of Na or by higher glomerular filtration rate. Intake, balance, and concentration of S in plasma were increased by the lower cation-anion difference at all stages of lactation. Excretion of HCO3- in urine was reduced by a lower dietary cation-anion difference at all stages of lactation, but secretion of protons in milk was reduced in late lactation only. Increasing dietary cation-anion difference does affect acid-base parameters in urine at all stages of lactation, but DMI and milk production of cows were affected in early and midlactation only.

Acid-Base Equilibrium↗
PubMed2000

Functional expression of a high affinity mammalian hepatic choline/organic cation transporter.

Uptake by the liver of the organic cation and essential nutrient choline is required for the hepatic synthesis of phosphatidylcholine. Uptake of other organic cations is also important for the metabolism and secretion of numerous endobiotics and drugs. Although a high affinity mammalian hepatic choline transporter has been kinetically defined, it has not been previously identified. We have developed stable transfectants of BALB/3T3 cells, using a murine member of the organic cation transporter gene family (mOct1/Slc22a1), and used these cells to characterize the transport of the organic cation choline and model organic cation tetraethylammonium (TEA). Functional expression of mOct1/Slc22a1 in BALB/3T3 cells confers the saturable, temperature-dependent uptake of choline with a K(m) of 42 micrometer, and uptake of TEA with a K(m) of 43 micrometer. We subsequently used our cell culture uptake system to kinetically define in HepG2 cells a high affinity choline uptake process, which transports choline with a K(m) similar to that of mOct1/Slc22a1 protein. We also demonstrated that organic cation transport by mOct1/Slc22a1 is inhibited by several organic cations, and that the gene is expressed in the perinatal period, at a time when phosphatidylcholine synthesis increases. We conclude that mOct1/Slc22a1 encodes a high affinity mammalian hepatic choline/organic cation transporter. This transporter may be important for hepatic phosphatidylcholine synthesis, and for the metabolism and secretion of many organic cationic drugs.

3T3 Cells↗
PubMed2001

[Cationization, a process for the delivery of antibodies to the central nervous system. Problems encountered in its application for immunotherapy strategies such as those for clostridial poisoning].

The central nervous system is separated from the rest of the body by the blood-brain barrier. This barrier prevents many substances, such as the antibodies, to penetrate into the brain making it difficult to use them for the treatment of brain diseases, such as tetanus and botulism. These two diseases are caused by the development of bacilli of the genus Clostridium which release neurotropic toxins. Specific antibodies can neutralize toxin activity when the toxin is in the blood but are ineffective when it is transported into nerve cells. Various invasive strategies have been used to deliver antibodies to the brain. However, they can induce seizures and transient neurologic deficits and may be applicable only for diseases restricted to the brain surface. Physiologically based strategies utilizing transport systems naturally present at the blood-brain barrier appear to be a more promising approach to brain delivery of antibodies. Cationization is a chemical treatment that causes the conversion of superficial carboxyl groups on a protein into extended primary amino groups. This is used to increase interactions of this protein with the negative charges at the luminal plasma membrane of the brain endothelial cells. The cationized protein can then undergo adsorptive mediated transcytosis through the blood-brain barrier. There are many problems yet to be solved in successfully carrying out in vivo applications of cationized antibodies. One of these problems is that cationization can cause damage to an antibody molecule and, thus, can compromise its binding affinity. Depending on the radiolabelling of the cationized antibodies, a serum inhibition phenomenon can possibly alter the pharmacokinetics and the organ distribution of these molecules. The antibodies can be cationized using various, synthetic (hexamethylenediamine) or naturally occuring (e.g., putrescine) polyamines. Hexamethylenediamine-induced and putrescine-induced brain uptakes of various antibodies and proteins have been shown, but the results obtained suggest that cationization with putrescine may be a more efficient approach to blood-brain barrier delivery. The development of animal or cellular models to check for therapeutic efficacy of cationized antibodies is necessary. In spite of the difficulties, the studies described in this paper indicate that cationization can be a realistic delivery strategy for carrying antibodies across the blood-brain barrier. The advances made in antibody technologies help generate more appropriate immunological structures for brain transfer with better effector functions and decreased immunogenicity or toxicity. Taken together, these two aspects can lead to further developments in treatment of intoxications caused by the clostridial neurotoxins.

Animals↗
PubMed1992

Sequestration of organic cations by acidified hepatic endocytic vesicles and implications for biliary excretion.

A number of cationic amine drugs that are taken up by liver and excreted into bile may accumulate in acidified intracellular organelles such as lysosomes and endosomes. These studies were undertaken to assess directly the uptake and accumulation of three types of model organic cationic amines by endocytic vesicles, and the role of vesicle acidification in this process. Uptake of tubocurarine (TC), vecuronium and tributylmethylammonium (TBuMA) by purified rat liver multivesicular bodies (MVB) (prelysosomal endocytic vesicles) was dependent upon MgATP, time and drug concentration. After 60 min, 52 to 81% of MVB cation content was dependent upon vesicle acidification (due to an electrogenic proton pump), but not upon an interior positive vesicle membrane potential. Nineteen to 42% of MVB cation content appeared due to binding to MVB membranes or to internal lipoproteins. Vesicle-to-medium ATP-dependent apparent concentration ratios for these three cations were 3.3 to 51. MVB uptake of these cations resembled uptake of methylamine, a tertiary amine known to distribute across organellar membranes according to pH gradients. By contrast, MVB uptake of the lipophilic quaternary amine methyldeptropine was not dependent upon MgATP or on development of MVB pH or membrane potential gradients. In further studies, TC, vecuronium and TBuMA were rapidly taken up by the isolated perfused rat liver and excreted in bile. Exposure to 250 mciroM primaquin (which partially alkalinized acidic endosomes and lysosomes) reduced accumulation of [3H]vecuronium in a lysosomal fraction by 23%, decreased perfusate disappearance of TC and TBuMA, but not of vecuronium, and decreased biliary appearance of all three cations. These studies suggest that acidified intracellular organelles sequester certain organic cationic drugs, possibly via a drug/proton antiporter, and/or diffusion followed by intravesicular protonation and trapping of tertiary amines. However, attempts at partial displacement of these drugs, accomplished through partial vesicle alkalization by primaquin, decreased excretion of TC, vecuronium and TBuMA, perhaps reflecting the small functional size of the displaceable organellar drug compartment and/or competition between primaquin and the organic cations for membrane transport processes.

Alkaline Phosphatase↗
PubMed1990

[In situ immune complex glomerulonephritis induced by perfusion of cationized antibody].

In situ immune complex glomerulonephritis can be induced in the rat employing cationized antigen planted in the glomerular basement membrane (GBM) as a target for specific antibody. Another possible mechanism of in situ immune complex formation is antibody already present in the GBM to bind circulating antigen. Present study was performed in order to determine whether cationized antibodies planted in the GBM could react with anionic as well as cationic antigens to form immune deposits. Horse ferritin, rabbit antibody to horse native ferritin (f-Ab) and rabbit antibody to ovalbumin (o-Ab) were highly cationized as described by Danon et al. The ability of the cationized antibodies to precipitate antigens was estimated by Ouchterlony analysis. 500 micrograms/100 g body weight (b.w.) of cationized f-Ab or o-Ab was perfused into the left renal artery of male Wistar rats and 0.1-10.0 mg/100 g b.w. of either native or cationized ferritin or ovalbumin was injected respectively into the tail vein 1 hr later. Estimation of proteinuria was done and the kidneys were removed up to 5 days for immunohistological as well as electron microscopical examination. Cationized antibodies bound to anionic sites of the GBM and combined with subsequently injected cationized ferritin or native ovalbumin in situ, both leading to formation of subepithelial immune deposit with activation of C3 and caused mild proteinuria. Native ferritin, however, induced neither subepithelial immune deposit nor proteinuria, because it didn't permeate through the GBM. The presented model indicates that antibody molecules of high positive charge can bind to the GBM and react with specific antigens that are traversing the barrier to form immune deposits. This is independent of the charge of antigen provided that the antigen molecules are permeable into the GBM, as is the case with ovalbumin but not native ferritin.

Animals↗
PubMed1990

Deoxygenation-induced cation fluxes in sickle cells: II. Inhibition by stilbene disulfonates.

Deoxygenation-induced cation movements in sickle cells were inhibited 80% to 85% by the anion transport inhibitor, 4,4'-diisothiocyano-2,2'disulfostilbene (DIDS). Morphologic sickling was not altered by DIDS treatment, demonstrating that morphologic sickling was not sufficient to produce cation leaks in sickle cells. DIDS inhibition of deoxygenation-induced cation flux was not affected when l- replaced Cl-, indicating that conductive anion movements did not limit cation flux in deoxygenated cells treated with DIDS. Inhibition was irreversible after preincubation with DIDS at 37 degrees C for 20 minutes, and was not affected by the oxygenation state of cells at the time of drug exposure. Sulfate self-exchange was inhibited at lower DIDS concentrations than was deoxygenation-induced flux. Incubation of cells with DIDS at 4 degrees C produced progressive blockade of sulfate exchange, but did not alter deoxygenation-induced cation fluxes. Other stilbene disulfonates, including compounds incapable of covalent reactions, also inhibited deoxygenation-induced cation movements, although several other inhibitors of anion exchange did not. Dissociation of the inhibition of anion exchange and deoxygenation-induced cation flux indicates that the DIDS effect on deoxygenation-induced cation movements does not involve the well-characterized stilbene binding site of the anion exchanger. These data provide evidence for a membrane constituent on the external surface of oxygenated sickle cells capable of interacting with DIDS to prevent the increase in cation permeability associated with sickling.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1987

The effect of monovalent cations on the pre-steady state reaction kinetics of bovine activated plasma protein C and des-1-41-light chain activated plasma protein C.

A pre-steady state kinetic analysis of the stimulation by monovalent cations of the activity of bovine activated protein C (APC) and a proteolytic fragment of APC, des-1-41-light chain activated protein C (GDAPC), toward the substrate, 4-methylumbelliferyl p-guanidinobenzoate, has been undertaken. With the cations Na+ and Cs+, at least two cation sites, or classes of sites, on APC were found to be important to the kinetic effects observed. For GDAPC, with both monovalent cations investigated, a single cation-binding site, or class of sites, of kinetic importance was discovered. The most general mechanism that fits all kinetic data was a rapid equilibrium type, with the cation(s) (A) and substrate (S) binding to the enzyme in a random fashion. Cations were found to be essential activators, and only formation of the EAS or EA2S complex led to product generation. For each enzyme, stimulation of the reaction rates was found to be chiefly due to a dramatic enhancement by monovalent cations of the rate constant (k2) for acylation of the enzyme since the dissociation constant (Ks) for enzyme-substrate interactions was increased in the presence of cations, and the deacylation rate constant (k3) was not affected by these activators.

Animals↗
PubMed1997

Intratumoral pharmacokinetics and in vivo gene expression of naked plasmid DNA and its cationic liposome complexes after direct gene transfer.

The pharmacokinetic properties and gene expression of naked plasmid DNA and its cationic liposome complexes were studied after direct intratumoral injection. Using a Walker 256 tissue-isolated tumor perfusion system, we quantified the recovery of naked plasmid DNA and cationic liposome complexes in the tumor, leakage from the tumor surface, and the venous outflow after intratumoral injection. Approximately 50% of naked plasmid DNA had been eliminated from the tumor 2 h after injection, whereas more than 90% of plasmid DNA was retained in the tumor when it was complexed with cationic liposomes. However, the distribution of these complexes in the tumor was restricted to the tissue surrounding the injection site. Pharmacokinetic analysis of the venous outflow profiles suggested that the rate-limiting process that determines the retention of plasmid DNA in the tumor is transferred from the injection site in the tumor tissue and that complexation with cationic liposomes may retard this process. Furthermore, we examined the gene expression of chloramphenicol acetyltransferase DNA constructs (naked pCMV-CAT) and the corresponding cationic liposome [3-beta-(N-(N',N'-dimethylaminoethane)carbamoyl)cholesterol] complexes. A similar level of gene expression was observed in vivo after direct intratumoral injection of naked DNA and its cationic liposome complexes. In both cases, a great variation was observed between tumors, and localization of gene-transduced cells in the tumor tissue was limited to the area in the vicinity of the injection site. Thus, these pharmacokinetic and gene expression studies have demonstrated that cationic liposomes can enhance the retention of injected DNA in the tumor model, whereas cationic liposome complex does not necessarily improve gene expression because of its poor dissemination in this tumor. The present study also suggested that there is a need to control the behavior of the injected naked plasmid DNA and its cationic liposome complexes to ensure better distribution throughout the tumor.

Animals↗
PubMed2001

A study of gas-phase reactions of radical cations of mono- and dihaloethenes with alcohols by FT-ICR spectrometry and molecular orbital calculations: substitution versus oxidation.

The ion-molecule reactions of the radical cations of vinyl chloride (1), vinyl bromide (2), 1,2-dichloroethene (3), 1,2-dibromoethene (4), 1,1-dichloroethene (5), and 1,1-dibromoethene (6) with methanol (MeOH) and ethanol (EtOH) have been studied by FT-ICR spectrometry. In the case of EtOH as reactant the oxidation of the alcohol to protonated acetaldehyde by a formal hydride transfer to the haloethene radical cation is the main process if not only reaction observed with the exception of the 1,2-dibromoethene radical cation which exhibits slow substitution. In secondary reactions the protonated acetaldehyde transfers the proton to EtOH which subsequently undergoes a well known condensation reaction of EtOH to form protonated diethyl ether. With MeOH as reactant, the 1,2-dihaloethene radical cations of 3.+ and 4.+ exhibit no reaction, while the other haloethene radical cations undergo the analogous reaction sequence of oxidation yielding protonated formaldehyde. Generally, bromo derivatives of haloethene radical cations react predominantly by substitution and chloro derivatives by oxidation. This selectivity can be understood by the thermochemistry of the competing processes which favors substitution of Br while the effect of the halogen substituent on the formal hydride transfer is small. However, the bimolecular rate constants and reaction efficiencies of the total reactions of the haloethene radical cations with both alcohols exhibit distinct differences, which do not follow the exothermicity of the reactions. It is suggested that the substitution reaction as well as the oxidation by formal hydride transfer proceeds by mechanisms which include fast and reversible addition of the alcohol to the ionized double bond of the haloethene radical cation which generates a beta-distonic oxonium ion as the crucial intermediate. This intermediate is energetically excited by the exothermic addition and fragments either directly by elimination of a halogen substituent to complete the substitution process or rearranges by hydrogen migration before dissociation into the protonated aldehyde and a beta-haloethyl radical. Reversible addition and hydrogen migrations within a long lived intermediate is proven experimentally by H/D exchange accompanying the reaction of the radical cations of vinyl chloride (1) and 1,1-dichloroethene (5) with CD3OH. The suggested mechanisms are substantiated by ab initio molecular orbital calculations.

Journal Article↗
PubMed1993

Uptake of metal cations by fibroblasts in vitro.

Atomic absorption spectroscopy was used to assess uptake of Ag+1, Au+4, Cd+2, Cu+2, In+3, Ni+2, Pd+2, and Zn+2 by in vitro cultures of Balb/c 3T3 fibroblasts as a function of concentration of the cations in cell-culture medium. Reversibility of this uptake was also measured. Metal cations exhibited a 400-fold difference in their tendency to accumulate in the cells; In+3 tended to accumulate the most, whereas Pd+2 accumulated the least. Uptake of the cations in the cells increased linearly with the concentration of the cation in the medium for all cations up to their 50% toxicity concentrations. Reversal of this uptake was slower than that of the initial uptake for three cations studied in more detail (Cd+2, In+3, and Ni+2). The duration of the initial exposure affected the proportion of the metal cations that were retained by the cells 5 h after the cations were removed from the medium. The proportion of retained Cd+2 did not change when the initial exposure was increased from 2 h to 6 h, whereas the proportion of retained In+3 decreased and Ni+2 increased over the same period. The tendency of the cells to accumulate these cations correlated with their cytotoxic potency (measured previously).

Animals↗
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↗
PubMed2005

Multiple charging of poly(propylene glycol) by binary mixtures of cations in electrospray.

Single, double and triple charging of poly(propylene glycol) (PPG) (Mn = 1900 g/mol) in the presence of binary mixtures of cations (Li+, Na+, K+, Cs+, and NH4+) under electrospray ionization (ESI) conditions were investigated. For these studies, sodium ion was selected as the reference cation, and the resulting ion-intensities were evaluated as a function of the [Na+]/[C+] ratio (where C+ is the other cation, i.e., Li+, K+, Cs+ and NH4+). A linear relationship was found between INa+/IC+)and [Na+]/[C+] (INa+ and IC+ stand for the intensity of the singly charged PPG molecules cationized with Na+ and C+ ions, respectively). The slope of the INa+/IC+--[Na+]/[C+] plot (alpha) indicates the binding selectivity of Na+ ions to PPG chains with respect to cation C+. In the case of the doubly charged PPG chains, the INaNa2+/INaC2+ and INaC2+/ICC2+ versus [Na+]/[C+] ratio also yield straight lines with slopes of approximately alpha/2 and 2alpha, respectively (INaNa2+, INaC2+ and ICC2+ are the intensity of the doubly charged PPG chains cationized with two Na+ ions, Na+ and C+ ions, and two C+ ions, respectively). Similarly, linear dependences with the [Na+]/[C+] ratio for the corresponding intensity ratios of the triply charged PPG were found. Based on the value of alpha, the selectivity of the cations was found to increase in the order of Li+ < Cs+ approximately Na+ < K+ approximately NH4+. The observed relative ion intensities are interpreted on the basis of the solution state equilibrium between PPG and the cations. In addition, the investigations showed that the abundances of the doubly and triply charged PPG-containing mixed cations can be optimized in a simple way using the value of alpha.

Journal Article↗
PubMed2000

The non-selective voltage-activated cation channel in the human red blood cell membrane: reconciliation between two conflicting reports and further characterisation.

Using the patch-clamp technique, the non-selective, voltage-activated cation channel in the human red blood cell (RBC) membrane was further characterised. Activity of the cation channel could be demonstrated at a range of salt concentrations with the current-voltage characteristics for monovalent cations going from linear to superlinear functions, depending on the cation concentration in the range of 100-500 mM. The non-selective voltage-activated cation channel was demonstrated to be permeable to the divalent cations Ca2+ and Ba2+, and even Mg2+. The current-voltage relations for the divalent cations were superlinear even at 75 mM salt concentration, but indicated outward rectification in contrast to the I-V curve for monovalent cations. The degree of activation at a given membrane potential depended strongly on the prehistory of the channel. The gating exhibited hysteretic-like behaviour, since the quasi steady-state deactivation and activation curves were displaced by approximately 25 mV. This result fully explains apparent discrepancies between V0.5-values previously obtained by slightly different experimental protocols. The possible physiological/pathophysiological role of the channel is discussed in the context of the demonstrated permeability for divalent cations.

Erythrocyte Membrane↗