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Biomedical subjects

S Sandberg

Publications and source records attributed to S Sandberg.

At least 127 records · Page 7Linked to original sources

Influence of tetracyclines on human polymorphonuclear leukocyte function.

Low concentrations of oxytetracycline, doxycycline, or minocycline (less than 10 micrograms/ml) did not influence in vitro polymorphonuclear leukocyte random migration, chemiluminescence, or glucose oxidation. At high concentrations of doxycycline or minocycline (greater than 10 micrograms/ml), chemiluminescence and glucose oxidation were impaired. High concentrations of doxycycline also reduced random migration. Oxytetracycline did not influence these functions in concentrations up to 100 micrograms/ml. The inhibiting effect of doxycycline and minocycline was abolished when 4 mM Mg2+ was added to the reaction mixture, and 4 mM Ca2+ partly restored minocycline-inhibited polymorphonuclear leukocyte functions. This indicates that the major effect of tetracyclines on in vitro polymorphonuclear leukocyte functions is mediated by their divalent cation chelating effect and that the results of in vitro experiments are highly dependent on the concentration of divalent cations in the reaction mixtures. The difference between the tetracyclines may be due to differences in lipid solubility, with solubility being highest for minocycline and lowest for oxytetracycline, or to different divalent cation chelating ability.

Cations↗

Effect of tetracyclines and UV light on oxygen consumption by human leukocytes.

When polymorphonuclear leukocytes were stimulated with zymosan, a sharp rise in oxygen consumption was observed. In the presence of doxycycline, we observed a further increase in oxygen consumption when the phagocytosing cells were exposed to UV light. When the light was turned off, oxygen consumption of the cells almost ceased, indicating photodamage to polymorphonuclear leukocytes during irradiation. Irradiation of the polymorphonuclear leukocytes for 20 min in the presence of doxycycline (10 micrograms/ml) before phagocytosis completely abolished the rise in oxygen consumption initiated by zymosan. Demethylchlortetracycline and light exposure also caused a marked reduction of polymorphonuclear leukocyte oxygen consumption, whereas oxytetracycline, lymecycline, chlortetracycline, and minocycline had only a slight or no photosensitizing effect. The photodamage induced by doxycycline and demethylchlortetracycline was inhibited by azide and enhanced in deuterium oxide. This was in accordance with singlet oxygen-mediated damage.

Humans↗

Light-induced release of protoporphyrin, but not of zinc protoporphyrin, from erythrocytes in a patient with greatly elevated erythrocyte protoporphyrin.

A patient with greatly increased erythrocyte protoporphyrin, but normal porphyrins in urine and feces, is described. The patient later developed a malignant lymphoma, and the reason why she accumulated protoporphyrin in her erythrocytes is not known. The protoporphyrin in the erythrocytes consisted of two types of protoporphyrin, free protoporphyrin (30%) and zinc protoporphyrin (70%). Upon irradiation of erythrocytes in the absence of albumin, protoporphyrin and zinc protoporphyrin, which were both bound to hemoglobin, were released. In contrast, when the irradiation was carried out in the presence of albumin, the photohemolysis was negligible, and there was release of free protoporphyrin, but not of zinc protoporphyrin, from the erythrocytes. In vivo albumin is present in the plasma and the results may help to explain why patients with erythropoietic protoporphyria (erythrocytes containing free protoporphyrin) are photosensitive, whereas patients with lead intoxication and iron deficiency (erythrocytes containing zinc protoporphyrin) are not.

Aged↗

Exponential increase in age-specific prevalence of ventricular dysrhythmia among males.

Analyzing nine available studies of cardiac dysrhythmia among males shows an exponential increase of the prevalence of dysrhythmia with increased age (16-74 yr). This pattern appears in unselected populations and in populations selected for prior history of myocardial infarction. In 6 of 9 population groups the exponent for the rate of increased prevalence of any ventricular premature contractions (VPCs) with age was statistically indistinguishable from study to study despite variations in length of monitoring, of local interpretations of ECG, or of differences in the composition of these groups. Within each population group the prevalence of "frequent" VPCs or of "complex" VPCs also increased exponentially with age. The precise mathematical expression for the increase suggests an etiologic explanation for cardiac dysrhythmia common to coronary artery disease and myocardial infarctions which exhibit similar behavior.

Adolescent↗

Light-induced protoporphyrin release from erythrocytes in erythropoietic protoporphyria.

The photohemolysis of normal erythrocytes incubated with protoporphyrin is reduced in the presence of albumin. When globin is added to normal erythrocytes loaded with protoporphyrin, protoporphyrin is bound to globin. During irradiation protoporphyrin moves from globin to the erythrocyte membrane and photohemolysis is initiated. Erythrocytes in patients with erythropoietic protoporphyria contain large amounts of protoporphyrin bound to hemoglobin. Upon irradiation of these cells in the absence of albumin, 40% of protoporphyrin and 80% of hemoglobin is released after 240 kJ/m2. The released protoporphyrin is hemoglobin bound. In contrast, when albumin is present only 8% of hemoglobin is released whereas protoporphyrin is released to 76%. The released protoporphyrin is albumin bound. A hypothesis for the release of erythrocyte protoporphyrin in erythropoietic protoporphyria without simultaneous hemolysis is proposed. Upon irradiation protoporphyrin photodamages its binding sites on hemoglobin, moves through the plasma membrane, and is bound to albumin in plasma.

Cell Membrane Permeability↗

Porphyrin-induced photodamage as related to the subcellular localization of the porphyrins.

In liver cells photodamage following externally added protoporphyrin affects predominantly membrane associated components, whereas photodamage by uroporphyrin also affects water-soluble components. Following excess endogenous production of porphyrins, protoporphyrin concentrates in the mitochondria and exerts its photodamaging effect primarily on the mitochondrial system, whereas uroporphyrin concentrates in lysosomes with release and inactivation of lysosomal enzymes when irradiated. The results may be of importance to explain the different skin lesions in porphyria cutanea tarda and erythropoietic protoporphyria.

Animals↗

Sideroblastic anemia with markedly increased free erythrocyte protoporphyrin without dermal photosensitivity.

A patient with idiopathic sideroblastic anemia and atypical clinical and biochemical findings is described. He had a greatly increased erythrocyte and plasma protoporphyrin, but normal urine and fecal porphyrins. The erythrocyte protoporphyrin had a fluorescence spectrum typical of free protoporphyrin, but caused no photosensitivity. Bone marrow metal chelatase activity was normal. There were no clinical signs of liver disease. The abnormal porphyrin metabolism in this patient is not known though a number of explanations are discussed.

Aged↗

Phototoxicity of protoporphyrin as related to its subcellular localization in mice livers after short-term feeding with griseofulvin.

In mice, feeding with griseofulvin leads to the rapid accumulation of protoporphyrin in liver mitochondria. When liver mitochondria from mice fed with griseofulvin for 2 days are exposed to irradiation (320-400 nm), uncoupling of oxidative phosphorylation followed by inhibition of respiration occurs at light doses above 3-5 kJ/m2. When combined preparations of mitochondria and lysosomes are irradiated, inactivation of enzymes occurs in the following order: succinate dehydrogenase greater than glutamate dehydrogenase greater than acid phosphatase greater than beta-glucuronidase. Qualitatively, the photodamaging effect of endogenously produced protoporphyrin is indistinguishable from that of externally added protoporphyrin. Quantitatively, however, when protoporphyrin is added externally, more protoporphyrin is taken up by lysosomes, and photoinactivation of the lysosomal enzymes is correspondingly more severe. The results are further evidence that porphyrin-induced photodamage is largely determined by the solubility properties of the porphyrins and the target structures [Sandberg & Romslo (1980) Biochim. Biophys. Acta 593, 187-195], and also that protoporphyrin-induced photodamage is essentially similar whether protoporphyrin is generated endogenously or added exogenously.

Animals↗

Protoporphyrin-induced photodamage to mitochondria and lysosomes from rat liver.

Preparations of mitochondria and lysosomes from rat liver were irradiated (340--380 nm) with light doses up to 80 kJ/m2 in the presence of 180 nmol/l protoporphyrin. ADP-stimulated respiration and succinate oxidation were inhibited before there was any significant release or inhibition of lysosomal enzymes. The results suggest that, rather than lysosomal lysis, damage to mitochondria may be the primary event in erythropoietic protoporphyria.

Animals↗

Porphyrin-induced photodamage at the cellular and the subcellular level as related to the solubility of the porphyrin.

Porphyrin-induced photodamage has been studied on small organic molecules, biomolecules, mitochondria and red cells. Water soluble components (e.g. tryptophan and glutamate dehydrogenase) are more easily destroyed by uroporphyrin than by protoporphyrin. On the other hand, lipophilic components (e.g. succinate dehydrogenase, mitochondria and red cell membranes) are more severely damaged by protoporphyrin. The results may be of importance to explain the different skin lesions in erythropoietic protoporphyria and in porphyria cutanea tarda. The photodamage is enhanced by D2O and reduced by azide. Reagents known to increase or decrease the yields of superoxide, peroxide or hydroxyl radicals have no effect on the photodamage. The results suggest that singlet oxygen is the most important reactive oxygen species.

Animals↗

Cerebrospinal fluid enzymes in neurological diseases.

The activities of adenylate kinase, creatine kinase and lactate dehydrogenase were measured in cerebrospinal fluid and serum from 127 patients admitted to the Department of Neurology. All cerebrospinal fluid samples with hemoglobin greater than 1 mg/l were excluded. Upper reference limits for the enzyme determinations were established, using samples from patients without objective criteria of organic involvement of the nervous system. High enzyme activities did not correlate to any particular group of diseases and were also found in patients without organic brain diseases. We conclude that determination of the three enzymes in cerebrospinal fluid is of limited value in the diagnosis of neurological diseases.

Adenylate Kinase↗

Porphyrin-induced photodamage to isolated human neutrophils.

Human neutrophils were irradiated with light at 340-380 nm in the presence of low concentrations of protoporphyrin or uroporphyrin. At increasing light doses or increasing concentrations of protoporphyrin, the neutrophils rapidly lost the ability of locomotion. Also, neutrophil chemiluminescence and hexose-monophosphate shunt activity rapidly declined. An early event was leakage of endogenous K(+) followed by lactate dehydrogenase and at a later stage leakage of particle-bound acid phosphatase. A number of cellular enzymes were inactivated, the susceptibility to inactivation decreased in the order: succinate dehydrogenase greater than lactate dehydrogenase greater than glutamate dehydrogenase greater than acid phosphatase. Uroporphyrin had no effect on neutrophil functions, leakage of K(+), or cellular enzymes. The results suggest that photodamage to the plasma membrane and the mitochondria are earlier events than photodamage to lysosomes.

Humans↗

Porphyrin-sensitized photodynamic damage of isolated rat liver mitochondria.

The respiration rates and the respiratory control ratios of isolated rat liver mitochondria have been measured following exposure to 0--160 kJ/m2 of near-ultraviolet radiation (blacklight) in the presence of low concentrations of porphyrins (0.1--0.2 mumol/l). Depending on the light dose, the concentration and the type of porphyrin, the following sequence of reactions occurred: uncoupling and inhibition of oxidative phosphorylation, energy dissipation, inhibition of respiration and swelling and disruption of the mitochondria. The detrimental effects could not be elicited in the absence of oxygen, neither could they be elicited by porphyrins or light alone. At equimolar concentrations, the effectiveness of the porphyrins as photosensitizers were: deuteroporphyrin greater than protoporphyrin much greater than coproporphyrin greater than uroporphyrin. The results may be of importance to explain the skin lesions seen when porphyrins of different hydrophobicity accumulate in the skin.

Animals↗

Effect of zinc on protoporphyrin induced photohaemolysis.

Zinc is readily inserted into protoporphyrin suspended either in a salt-sucrose buffered solution or endogenously present in red cell haemolysate in erythropoietic protoporphyria. Red cells from healthy persons were incubated with metal-free protoporphyrin or zinc-protoporphyrin and irradiated with light at 360-470 nm. The photohaemolysis was significantly less with zinc-protoporphyrin compared with that of the metal-free protoporphyrin. The results are discusssed in relation to the possibility of using zinc as a photoprotective and hepatoprotective agent in erythropoietic protoporphyria.

Animals↗