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Biomedical subjects

P Saltman

Publications and source records attributed to P Saltman.

At least 37 records · Page 2Linked to original sources
PubMed1990

Time-dependent modifications of ferric-adriamycin.

The biological and chemical properties of the ferric-Adriamycin complex changed with time after its preparation. Our experiments demonstrated that the toxicity of the iron-chelate in mice decreased as a function of its age. The reduced toxicity can be correlated with changes in the difference spectrum of ferric-Adriamycin vs Adriamycin (ADR), where a peak around 610 nm shifted to the 570 nm region. When ferric-Adriamycin "aged", the affinity of the drug for iron increased. Concurrently, the redox properties of the chelate changed, such that the bound iron was no longer reduced by glutathione or cysteine. The time-dependent changes observed did not involve the formation of polynuclear iron, as shown by electron spin resonance. Thin-layer chromatography showed that ADR undergoes accelerated degradation in the presence of iron. The iron-catalyzed degradation was oxygen independent. The changes evolving in the spectral and chemical properties of the chelate were shown to stem from transfer of the iron from ADR to one of the degradation products.

Anaerobiosis↗
PubMed1990

Long-term estrogen replacement therapy in postmenopausal women sustains vertebral bone mineral density.

The cross-sectional relationship between long-term estrogen use and vertebral (L2-4) bone mineral density (BMD) was determined in 65 postmenopausal white women between 55 and 75 years who were at least 10 years from their menopause. Long-term estrogen users began therapy within 5 years of menopause and continued for a duration of at least 10 years. The mean duration of use was 19.8 years. Controls used estrogen for less than 1 year. There was a significant difference (p less than 0.02) in mean spinal BMD between estrogen users (1.219 g/cm2) and controls (1.092 g/cm2). There was no significant difference in age, height, weight, or dietary calcium (Ca) intake between the two groups. The statistical difference in BMD was retained when (1) 23 estrogen users were paired with age-matched controls, (2) only women with a natural menopause or history of bilateral oophorectomy were included, and (3) only women with a natural menopause were compared. A spinal BMD below the estimated fracture threshold of 0.965 g/cm2 was found in 11 of 40 controls and only 2 of 25 estrogen users. Comparison of estrogen users with a natural menopause to those with bilateral oophorectomy revealed no significant difference in BMD. These data confirm the salutary effect of long-term estrogen use in the maintenance of vertebral bone mass in postmenopausal women.

Aged↗
PubMed1990

Zinc--a redox-inactive metal provides a novel approach for protection against metal-mediated free radical induced injury: study of paraquat toxicity in E. coli.

The essential mediatory role of copper and iron in a variety of free radical-induced injuries, including paraquat-induced biological damage has been recently demonstrated. It was postulated that these transition metals undergo cyclic redox reactions, and serve as centers for repeated production of hydroxyl radical, which are the ultimate deleterious agents. Additionally, we had presented evidence indicating efficient protection against paraquat toxicity by agents commonly employed (chelators, chemical scavengers and protecting enzymes). In this study we have used the E. coli model in order to develop a new approach for protection against paraquat-induced metal-mediated cellular injury. It entails the administration of excess zinc (up to 50 fold over copper), which results in an inhibition of the toxic effect of paraquat. Lineweaver- Burk analysis demonstrates the competitive mode of this inhibition. The suggested mechanism involves the displacement of the redox-active copper (or iron) from its binding site and by this diverting the site of repeated production of free radicals. Thus, use of redox-inactive metals, which possess high similarity of their ligand chemistry, to that of iron and copper but are of relative low toxicity by themselves, should be considered for intervention in paraquat toxicity and in other metal-mediated free radical-induced injurious processes.

Binding Sites↗
PubMed1990

The effect of zinc on reperfusion arrhythmias in the isolated perfused rat heart.

Considerable evidence suggests that free radicals engendered by redox-active metals, particularly iron and copper, are causative agents in reperfusion injury following ischemia. This study demonstrates that perfusion of the isolated rat heart with a buffer containing zinc, a non-redox active metal similar to copper in its coordination chemistry, inhibits the development of ventricular arrhythmias during reperfusion. Zinc was employed as the bishistidine complex, Zn--His2, to maintain solubility and permeability. Zn--His2 exerted an antiarrhythmic activity as hearts spent a longer time in normal sinus rhythm and a shorter time in ventricular fibrillation during reperfusion following 10 min of regional ischemia. However, Zn--His2 also produced a negative inotropic and chronotropic effect, evident during equilibration and ischemia. In the course of experiments which began in Israel and continued in the U.S. it was necessary to use two different sources of rats. Hearts from the two sources manifested different sensitivities to the concentrations of Zn--His2, although their physiological effects were similar. Differential activity responses were noted for antiarrhythmic activity, negative inotropic and chronotropic properties, and toxicity. In both groups of untreated hearts the incidence of ventricular fibrillation after ischemia was 100%. Ventricular fibrillation was reduced to 17% at 37.5 microM Zn--His2 in the U.S.-bred rat hearts and to 9% at 200 microM Zn--His2 in those from Israel. These changes in Zn--His2 treated animals were accompanied by a decrease in lactate dehydrogenase release from the myocardium during reperfusion. None of the protective effects was due to histidine alone. These results indicate that zinc prevents ventricular arrhythmias during reperfusion following regional ischemia and may prevent membrane damage, possibly, by reduction of free radical formation.

Animals↗
PubMed1989

Oxidative damage to human red cells induced by copper and iron complexes in the presence of ascorbate.

The role of trace metals in the generation of free radical mediated oxidative stress in normal human red cells was studied. Ascorbate and either soluble complexes of Cu(II) or Fe(III) provoked changes in red cell morphology, alteration in the polypeptide pattern of membrane proteins, and significant increases in methemoglobin. Neither ascorbate nor the metal complexes alone caused significant changes to the cells. The rate of methemoglobin formation was a function of ascorbate and metal concentrations, and the chemical nature of the chelate. Cu(II) was about 10-times more effective than Fe(III) in the formation of methemoglobin. Several metals were tested for their ability to compete with Cu(II) and Fe(III). Only zinc caused a significant inhibition of methemoglobin formation by Fe(III)-fructose. These observations suggest that site-specific as well as general free radical damage is induced by redox metals when the metals are either bound to membrane proteins or to macromolecules in the cytoplasm. The Cu(II) and Fe(III) function in two catalytic capacities: (1) oxidation of ascorbate by O2 to yield H2O2, and (2) generation of hydroxyl radicals from H2O2 in a Fenton reaction. These mechanisms are different from the known damage to red cells caused by the binding of Fe(III) or Cu(II) to the thiol groups of glucose-6-phosphate dehydrogenase. Our system may be a useful model for understanding the mechanisms for oxidative damage associated with thalassemia and other congenital hemolytic anemias.

Ascorbic Acid↗
PubMed1989

Zinc protects Escherichia coli against copper-mediated paraquat-induced damage.

The essential mediatory role of copper and iron in paraquat-induced biological damage has been recently demonstrated. It was postulated that these transition metals undergo cyclic redox reactions and serve as centers for repeated production of hydroxyl radical, which are the ultimate deleterious agents. Additionally, we had presented evidence indicating efficient protection against paraquat toxicity by agents commonly employed (chelators, chemical scavengers, and protecting enzymes). In this study we have used the Escherichia coli model in order to develop a new approach for protection against paraquat-induced metal-mediated cellular injury. It entails the administration of excess zinc (up to 50-fold over copper), which results in an inhibition of the toxic effect of paraquat. Lineweaver-Burk analysis demonstrates the competitive mode of this inhibition. The suggested mechanism involves either the direct displacement of copper by zinc or the formation of a ternary complex, (formula; see text) in which the binding of Cu(II) is weakened by the binding of Zn(II), interfering with the copper-mediated free radicals formation. Thus, use of redox-inactive metals, which possess high similarity of their ligand chemistry to that of iron and copper but are of relative low toxicity by themselves, should be considered for intervention in paraquat toxicity and in other metal-mediated free radical-induced injurious processes.

Copper↗
PubMed1989

A comparison of quantitative dual-energy radiographic absorptiometry and dual photon absorptiometry of the lumbar spine in postmenopausal women.

Noninvasive bone densitometry is an important aspect in the detection and management of osteoporosis and other forms of metabolic disease of calcified tissue. A system using quantitative dual-energy digital projection radiography (QDR) of the lumbar spine was systematically tested against dual-photon absorptiometry (DPA) of the lumbar spine in 131 women over 55 years of age and free from major risk factors for osteoporosis. All subjects were scanned by both QDR and DPA under the same conditions. Measurements for a given subject were made within 15 minutes of each other. Bone mineral densities (BMD) were determined for four individual levels in the lumbar spine (L1-L4). Regression equations for BMD vs. age, height, and weight were calculated. The results of this investigation indicate that DPA- and QDR-derived BMD values are comparable. BMD values derived by QDR were consistently lower than those obtained by DPA (DPA = 1.115 QDR + 0.137, r = 0.942). The L2 lumbar region was the most strongly correlated determination.

Absorptiometry, Photon↗
PubMed1989

Deleterious synergistic effects of ascorbate and copper on the development of Plasmodium falciparum: an in vitro study in normal and in G6PD-deficient erythrocytes.

The effects of ascorbate and copper on the development of Plasmodium falciparum were studied in two modes: pretreatment of uninfected erythrocytes followed by infection by P. falciparum and treatment of parasitized erythrocytes. Pretreatment of G6PD(+) cells with ascorbate caused a slight enhancement in parasite development, while in G6PD(-) cells a suppressive effect on the plasmodia was demonstrated. Copper alone interfered with parasite growth in both cell types. The combination of copper and ascorbate arrested parasite maturation, an effect which was more pronounced in G6PD(-) cells. Synergism between copper and ascorbate was better demonstrated following the treatment of infected erythrocytes: while ascorbate alone supported parasite development and copper alone had only a marginal suppressive effect, the combination of copper and ascorbate yielded a marked inhibition of parasite growth. Ascorbate proved destructive to the parasites in the presence of adventitious copper, or on the second day of the parasite life cycle. In these cases it acted as a pro-oxidant, while in other systems, in particular in the presence of a chelator, ascorbate acted as an antioxidant and promoted parasite growth. The understanding of the role of transition metals and free radicals in parasite development and injury could shed light on novel approaches to fight malaria.

Animals↗
PubMed1989

Preliminary report of decreased serum magnesium in postmenopausal osteoporosis.

Serum, red cell, urinary and bone Mg levels have been measured in 10 post-menopausal osteoporotics. Osteoporosis was confirmed by clinical fracture, histological analysis and dual-photon absorptiometry quantification. When compared to a healthy population matched for age and sex, serum Mg levels were statistically significantly (p less than 0.05) lower in osteoporotics (0.82 +/- 0.06 mmol/l) compared to normal subjects (0.87 +/- 0.04 mmol/l). No difference appeared for red cell, urinary or bone Mg determination. If these results are confirmed in a long-term study, serum Mg might be added to a batch of tests used to discriminate a subset of patients with an increased risk of developing postmenopausal osteoporosis.

Aged↗
PubMed1987

Electron transfer from cytochrome b5 to iron and copper complexes.

The rates of electron transfer from the tryptic fragment of bovine liver cytochrome b5 to FeIIINTA, FeIIIATP, CuIINTA, CuIIATP, and CuIIHis have been measured by anaerobic stopped-flow techniques. The rates of reduction of the Fe(III) complexes are independent of ionic strength, enhanced at low pH, and slightly inhibited by ZnIINTA. Saturation kinetics are observed with CuIINTA (kappa et = 0.05 s-1, K = 8.6 M-1), CuIIHis (kappa et = 0.2 s-1, K = 2.6 X 10(3) M-1), and CuIIATP (kappa et = 0.6 s-1, K = 4.5 X 10(3) M-1), thereby indicating that binding of Cu(II) to the protein occurs prior to electron transfer. 1H NMR resonances of the three surface histidines and some neighboring residues have been assigned by two-dimensional NMR techniques. NMR titration experiments show unequivocally that CuIINTA binds preferentially at a site near His-26 and Tyr-27.

Animals↗
PubMed1987

Isolation and characterization of a new zinc-binding protein from albacore tuna plasma.

The protein responsible for sequestering high levels of zinc in the plasma of the albacore tuna (Thunnus alalunga) has been isolated by sequential chromatography. The glycoprotein has a molecular weight of 66,000. Approximately 8.2% of its amino acid residues are histidines. Equilibrium dialysis experiments show it to bind 3 mol of zinc/mol of protein. The stoichiometric constant for the association of zinc with a binding site containing three histidines was determined to be 10(9.4). This protein is different from albumin and represents a previously uncharacterized zinc transport protein.

Amino Acids↗
PubMed1987

Kinetics and mechanisms of the oxidation of myoglobin by Fe(III) and Cu(II) complexes.

Two distinct mechanisms by which sperm whale myoglobin reduces, respectively, complexes of Fe(III) and Cu(II) and, in turn, is oxidized to metmyoglobin have been characterized. For both mechanisms, deoxymyoglobin is the active reductant. An outer sphere electron transfer, probably at the edge of the heme, is involved for Fe(III)NTA (NTA is nitrilotriacetic acid). This pathway does not involve ionic binding of the Fe(III) complex to the protein. The most reactive species of Fe(III)NTA is uncharged. No inhibition is observed with Ni(II) or Zn(II). An outer sphere site specific electron transfer is operative for reduction of Cu(II) complexes. The site has been characterized using NMR spectroscopy and involves one or more histidines. There is an initial binding of the Cu(II) chelate. The ternary complex of chelator-Cu(II)-deoxymyoglobin is a mandatory intermediate. Ni(II) and Zn(II) compete with Cu(II) for the binding site. A scheme for the participation of either or both of these mechanisms in reduction reactions of heme proteins is proposed. Both the overall redox potential, delta E0, and the stability constant for the ternary complex, K, govern the pathway and the reaction rate.

Binding Sites↗
PubMed1987

The effect of deficiencies of manganese and copper on osteoinduction and on resorption of bone particles in rats.

Subcutaneous implantation of devitalized demineralized bone powers (DBP) and mineral-containing bone particles (BP) into rats raised on either a control (C), low manganese and low copper (L), or manganese-deplete (D) diet, allowed the separate evaluation of bone formation and of bone resorption, respectively. DBP failed to induce chondrogenesis or osteogenesis in D rats. Cartilage formation was delayed in the L rats compared to C rats. There was significantly less resorption of BP by L and D rats than C rats. These results show multiple cellular effects of long-term manganese (Mn) and copper (Cu) deficiencies on bone metabolism including decreased osteogenesis and a decrease in osteoclast activity.

Aging↗
PubMed1987

Serum zinc is unaffected by effective captopril treatment of hypertension.

Captopril, a sulfhydryl compound that lowers blood pressure by inhibiting the zinc metalloenzyme, angiotensin converting enzyme, may occasionally result in ageusia, a symptom also associated with zinc deficiency. We therefore studied serum zinc and copper concentrations in a group of 14 essential hypertensive subjects before treatment and after 5-6 months of antihypertensive oral monotherapy with either captopril (50 mg, twice daily; n = 7) or other drugs (propranolol or alphamethyldopa; n = 7). Serum zinc and copper were unaltered by either regimen. Thus, zinc depletion is an unlikely consequence of long-term exposure to captopril, at least in the dosages commonly used for treatment of hypertension.

Blood Pressure↗
PubMed1986

A digestion bomb for wet ashing biological materials.

The design and construction of a wet digestion chamber resistant to acids and bases for hard and soft tissues is described. Loss of volatile elements is prevented. Reproducible complete recoveries for a variety of inorganic metal ions are routinely achieved.

Acids↗
PubMed1986

Age-related differences in the bone mineralization pattern of rats following exercise.

The effect of 12 weeks of treadmill exercise on the mineralization of trabecular and cortical bone was studied in rats 7, 14, and 19 months of age. Bone mineralization was evaluated by measuring concentrations of Ca, Mg, and hydroxyproline as well as uptake of 45Ca concentration in the femur, humerus, rib and calvaria. The 7- and 14-month-old rats increased mineralization in those cortical bones directly involved in exercise. The 19-month animal responded to exercise by increasing mineralization in all bones examined, including the nonweight bearing trabecular calvaria and cortical rib. From these data, it is apparent that the older animals undergo a total skeletal mineralization in response to exercise compared with local adaptation in the younger animal. Further, we provide evidence to support the use of the rat as a model in which to study mammalian bone physiology during the aging process.

Aging↗
PubMed1986

Effects of long-term dietary manganese and copper deficiency on rat skeleton.

Experiments were designed to produce biochemical changes in both serum and bone in rats by long-term dietary deficiencies of manganese (Mn) and copper (Cu). Weanling rats were fed one of three diets: 1) normal Mn and Cu (N), 2) low Mn and Cu (L) and 3) depleted Mn and normal Cu (D). After 12 mo, serum Ca and P were significantly greater in the D rats than the N rats (134, 50 mg/L and 103, 39 mg/L, respectively). Serum and femur Mn levels were lower in D rats than in normal rats. Serum and femur Cu levels were lower in L rats than N rats. Femur Ca concentrations were significantly lower in D rats than in N rats (180 and 272 mg/g, respectively). Radiographic differences could be detected in some rats fed the L and D diets. In the two deficient groups, increased serum Ca was negatively correlated with bone Ca (r = -0.69; P less than 0.01). This biochemical association may represent alterations in regulatory control of Ca at the level of the bone (decreased mineralization) combined with an increase in bone resorption. The effect of long-term dietary deficiencies in Mn and Cu should be considered in human bone metabolism.

Animal Nutritional Physiological Phenomena↗