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M Dalmark

Publications and source records attributed to M Dalmark.

At least 37 records · Page 2Linked to original sources
PubMed1983

Doxorubicin (Adriamycin) transport in Ehrlich ascites tumour cells: comparison with transport in human red blood cells.

The doxorubicin (Adriamycin) transport was investigated in murine Ehrlich ascites tumour cells by measuring the initial rate of cellular net uptake in vitro at 37 degrees C (pH 7.3). Transport characteristics were compared with previously published data on doxorubicin transport in human red blood cells. The apparent permeability coefficient in ascites cells (2.4 X 10(-5) cm sec-1) and in red cells was of the same order of magnitude when calculated from the initial influx into cells suspended in a salt solution (37 degrees C, pH 7.3). Doxorubicin was strongly adsorbed to the cell surface of ascites cells in contrast to the doxorubicin adsorption to red cells when the cells were suspended in a salt solution. The adsorbed doxorubicin could be removed by washing the ascites cells either with DNA or with human albumin salt solutions indicating that the adsorption to cell surface components was reversible. Cell membrane modifiers, 1-alcohols, local anaesthetics, phloretin, HgCl2, para-chloromercuribenzoate, affected doxorubicin transport in ascites tumour cells and red cells in the same manner as these modifiers affected the transport of other lipophilic compounds. Ehrlich ascites tumour cells and human red blood cells appeared to represent two extremes with regard to doxorubicin adsorption to cell surfaces but doxorubicin seems to pass through the rate limiting barrier of the cell membrane by simple diffusion of the uncharged doxorubicin molecule in both cell types.

1-Octanol↗
PubMed1982

Molecular association between doxorubicin (adriamycin) and DNA-derived bases, nucleosides, nucleotides, other aromatic compounds, and proteins in aqueous solution.

Doxorubicin (adriamycin) forms molecular associations with other aromatic and planar molecules (hetero-association) and with other doxorubicin molecules (self-association) in aqueous solution. The ability of doxorubicin to form complexes was demonstrated in a nonbiological system by measuring the doxorubicin partition coefficient. A decreased apparent doxorubicin activity coefficient in the presence of complex formation was also demonstrated in a biological system by measuring the transmembranous doxorubicin transport and the doxorubicin distribution at equilibrium in human red blood cells and their suspending medium. Doxorubicin formed complexes in aqueous solution at 37 degrees (pH 7.3) with (a) DNA-derived bases, nucleosides, and nucleotides; (b) amino acids such as tryptophan; (c) proteins such as human serum albumin and hemoglobin; and (d) a broad range of biologically active compounds such as NAD, propanthelline, caffeine, chloroquine, imipramine, and propranolol. The apparent thermodynamic quantities of the complex formation with adenosine 5'-triphosphate were delta H0, -9.5 kcal . mole-1; delta S0, -19 eu . mole-1; and delta G0 (310 degrees K), -3.6 kcal . mole-1. The binding forces of the molecular associations were probably hydrophobic (short-range force), sometimes supported by electrostatic interaction (long-range force).

Chemical Phenomena↗
PubMed1981

A Fickian diffusion transport process with features of transport catalysis. Doxorubicin transport in human red blood cells.

The transport of the antineoplastic drug doxorubicin (Adriamycin) in human red blood cells was investigated by measuring the net efflux from loaded cells. Previous data indicated that doxorubicin transport was a Fickian diffusion transport process of the electrically neutral molecule through the lipid domain of the cell membrane (Dalmark, 1981 [In press]). However, doxorubicin transport showed saturation kinetics and a concentration-dependent temperature dependence with nonlinear Arrhenius plots. The two phenomena were related to the doxorubicin partition coefficient between 1-octanol and a water phase. This relationship indicated that the two phenomena were caused by changes in the physiochemical properties of doxorubicin in the aqueous phase and were not caused by interaction of doxorubicin with cell membrane components. The physicochemical properties of doxorubicin varied with concentration and temperature because of the ability of doxorubicin to form polymers by self-association in aqueous solution like other planar aromatic molecules through pi-electron orbital interaction. The hypothesis is proposed that doxorubicin transport across cell membranes takes place by simple Fickian diffusion.

Biological Transport↗
PubMed1981

Characteristics of doxorubicin transport in human red blood cells.

The doxorubicin (Adriamycin) transport was investigated by measuring the net efflux of dororubicin from loaded erythrocytes into doxorubicin-free media at 37 degree C. The doxorubicin concentration in the cell water was kept low (5-10 mumol/l). The doxorubicin transport increased with increasing pH. The approx. pKa of the doxorubicin amino group was 7.6(37 degree C, ionic strength 0.15). Phloretin, l-alcohols and local anaesthetics increased doxorubicin transport after the fashion of the effect of these drugs on membrane transport of lipophilic compounds. Several inhibitors of facilitated transport systems in erythrocytes did not affect doxorubicin transport. The calcium and magnesium concentration in the cell water (0-2 mmol/l) did not affect doxorubicin transport. It appears that doxorubicin transport in human erythrocytes takes place by free diffusion of the electrically uncharged (unprotonated) doxorubicin molecule through the lipid domain of the cell membrane.

Alcohols↗
PubMed1981

The effect of ionic strength on cell volume, cell pH and cellular buffer capacity in human red blood cells.

The effect of ionic strength on the properties of high molecular weight molecules in human red cells is described. The ionic strength was varied by dialysis of freshly drawn red cells against various KCl solutions in the presence of the ionophore nystatin. Nystatin increased the membrane permeability rather unspecifically towards both monovalent cat- and anions. The membrane permeability towards molecules with an Stokes-Einstein radius of more than 4 A was unaltered. With increasing ionic strength the cellular pH and the cellular volume increased, while the cellular buffer capacity decreased. The variation of the chloride distribution ratio with pH at various KCl concentrations is given in a tabulated form.

Buffers↗
PubMed1979

Chloride transport by self-exchange and by KCl salt diffusion in gramicidin-treated red blood cells.

The permeability of gramicidin-treated human red blood cell membranes to K+ and Cl- has been measured at normal ionic strength (1) by tracer exchange at steady-state distribution of salt, and (2) by net transport of salt in the presence of a salt concentration gradient. Under both conditions KCl was the only inorganic salt in cells and medium. In the studies of self-exchanges the electrical driving force on the ions was zero. Calculaton of permeability coefficients from net salt transport was simplified because the experiment was designed as a special case of the Nerst-Planck diffusion regime, i.e. the single salt case. Gramicidin altered the cell membranes from being anion to become cation selective. Gramicidin increased the potassium exchange without affecting the chloride exchange measurably. The chloride exchange showed saturation kinetics as does chloride exchange in normal cells. The net transport of KCl in the presence of a constant concentration gradient increased to a constant value with increasing gramicidin concentration. At high gramicidin concentrations (0 degree C, pH 7.2) the "chloride permeability coefficient" calculated from tracer exchange (1.9 x 10(-6) cm/s) was 290 times the chloride permeability coefficient calculated from net salt transport (0.65 x 10(-8) cm/s). The latter value corresponds to a chloride conductance of 4.2 x 10(-6) ohm-1 cm-2. The chloride permeability coefficient was 2.1 x 10(-6) cm/s at 25 degrees C (pH 6.8) indicating a value of 3 for the Q25. It appears that normal red cells are anion selective in the sense that anion permeability exceeds cation permeability with a factor of more than a hundred between 0 degrees C and body temperature. The anion exchange, i.e. the Hamburger shift, is a tightly coupled transport process which is several orders of magnitude faster than anion transport by salt diffusion.

Biological Transport↗
PubMed1976

Effects of halides and bicarbonate on chloride transport in human red blood cells.

Chloride self-exchange was determined by measuring the rate of 36Cl efflux from human red blood cells at pH 7.2 (0 degrees C) in the presence of fluoride, bromide, iodide, and bicarbonate. The chloride concentration was varied between 10--400 mM and the concentration of other halides and bicarbonate between 10--300 mM. Chloride equilibrium flux showed saturation kinetics. The half-saturation constant increased and the maximum flux decreased in the presence of halides and bicarbonate: the inhibition kinetics were both competitive and noncompetitive. The competitive and the noncompetitive effects increased proportionately in the sequence: fluoride less than bromide less than iodide. The inhibitory action of bicarbonate was predominantly competitive. The noncompetitive effect of chloride (chloride self-inhibition) on chloride transport was less dominant at high inhibitor concentrations. Similarly, the noncompetitive action of the inhibitors was less dominant at high chloride concentrations. The results can be described by a carrier model with two anion binding sites: a transport site, and a second site which modifies the maximum transport rate. Binding to both types of sites increases proportionately in the sequence: fluoride less than chloride less than bromide less than iodide.

Bicarbonates↗
PubMed1975

Chloride transport in human red cells.

1. The chloride equilibrium flux (chloride self-exchange) was determined by measuring the rate of 36Cl efflux from radioactively labelled human red cells. The cellular chloride concentration was varied between 5 and 700 mM by the nystatin technique (Cass & Dalmark, 1973). The chloride transport capacity was not affected by the nystatin technique. 2. The chloride equilibrium flux showed saturation kinetics in the pH range between 6-2 and 9-2 (0 degrees C). The chloride transport decreased at chloride concentrations higher than those which gave the maximum transport. 3. The apparent half-saturation constant, (K1/2), depended on the pH and whether the chloride transport was perceived as a function of the chloride concentration in the medium or in the cell water. The (K1/2)m increased and the (K1/2)c decreased with increasing pH. The dependence of the chloride transport on the chloride concentration was described by Michaelis-Menten kinetics at pH 7-2, but at values of pH outside pH 7-8 S-shaped or steeper graphs were observed. 4. The chloride equilibrium flux varied with the pH at constant chloride concentration in the medium (pH 5-7-9-5). The transport had a bell-shaped pH dependence at chloride concentrations below 200 mM. At chloride concentrations between 300 and 600 mM the chloride transport increased with increasing pH to reach a plateau around pH 8. The position of the acidic branches of the pH graphs was independent of the chloride concentration (25-600 mM), but the position of the alkaline branches moved towards higher values of pH with increasing chloride concentration (5-150 mM). Thus, the position of the pH optimum increased with increasing chloride concentration. The chloride transport at low pH values was a function of the inverse second power of the hydrogen ion concentration. The pK of the groups which caused the inhibition was approximately 6 and independent of the temperature (0-18 degrees C). 5. The chloride equilibrium flux as a function of chloride concentration, pH, and temperature could be described by a transport model with a mobile, positively charged, chloride binding carrier with a single chloride dissociation constant of 33 mM, a transport capacity of 900 m-mole/3 x 10(13) cells.min (pH 7-2, 0 degrees C), and an Arrhenius activation energy of 30 kcal/mole. The pH dependence of the transport of inorganic monovalent and divalent anions is discussed in relation to the suggested model.

Biological Transport↗
PubMed1975

Chloride and water distribution in human red cells.

1. The influence of the pH and the temperature on the cellular chloride and water content was investigated in human red cells, the cellular KC1 concentrations of which varied between 10 and 600 mM. The compositions of the media (10-600 mM-KC1, 1 mM-NaC1, 27 mM sucrose) at each single KC1 concentration were constant at the different values of the pH and the temperature. 2. The variation of the cellular KC1 concentration was obtained by washing the cells with KC1 salt solutions containing nystatin...

Cell Membrane Permeability↗
PubMed1973

Characteristics of chloride transport in human red blood cells.

The efflux of chloride-36 from human erythrocytes under steady-state conditions is a saturable process that is competitively inhibited by bicarbonate and noncompetitively inhibited by acetate. This chloride self-exchange flux is reversibly dependent on the pH of the medium between 5.7 and 9.6 with a maximum flux at pH 7.8. The increase in chloride flux between pH 5.7 and 7.8 is inexplicable by the fixed charge hypothesis. The interpretations are made that chloride transport in human erythrocytes is carrier mediated, that bicarbonate utilizes the same transport mechanism, and that the mechanism can be titrated with hydrogen ions into less functional forms for chloride transport.

Acetates↗
PubMed1972

Temperature dependence of chloride, bromide, iodide, thiocyanate and salicylate transport in human red cells.

1. The temperature dependence of the steady-state self-exchange of chloride between human red cells and a plasma-like electrolyte medium has been studied by measuring the rate of (36)Cl(-) efflux from radioactively labelled cells. Between 0 and 10 degrees C the rate increased by a factor of eight corresponding to an Arrhenius activation energy of 33 kcal/mole.2. The rate of chloride exchange decreased significantly in experiments where 95% of the chloride ions in cells and medium were replaced by other monovalent anions of a lyotropic series. The rate of chloride self-exchange was increasingly reduced by bromide, bicarbonate, nitrate, iodide, thiocyanate, and salicylate. The latter aromatic anion was by far the most potent inhibitor, reducing the rate of chloride self-exchange to 0.2% of the value found in a chloride medium.3. The temperature sensitivity of the chloride self-exchange was not affected significantly by the anionic inhibitors. The Arrhenius activation energies of chloride exchange were between 30 and 40 kcal/mole in the presence of the six inhibitory anions mentioned above.4. The rate of self-exchange of bromide, thiocyanate, and iodide between human red cells and media was determined after washing and labelling cells in media containing 120 mM bromide, thiocyanate, or iodide respectively. The rate of self-exchange of the three anions were 12, 3, and 0.4% of the rate of chloride self-exchange found in the chloride medium.5. The Arrhenius activation energies of the self-exchange of bromide, iodide, and thiocyanate were all between 29 and 37 kcal/mole, the same magnitude as found for the self-exchange of chloride.6. Although approximately 40% of the intracellular iodide and salicylate ions appeared to be adsorbed to intracellular proteins, the rate of tracer anion efflux followed first order kinetics until at least 98% of the intracellular anions had been exchanged.7. The self-exchange of salicylate across the human red cell membrane occurred by a different mechanism than the one utilized by the inorganic monovalent anions. The activation energy of salicylate exchange (13.2 kcal/mole) was significantly lower than that of inorganic anion exchange. Salicylate exchange increased with decreasing pH in contrast to the exchange of chloride, which decreases when pH is lowered.

Adsorption↗