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Biomedical subjects

L R Solomon

Publications and source records attributed to L R Solomon.

At least 37 records · Page 2Linked to original sources
PubMed1989

Studies on the mechanism of acetaldehyde-mediated inhibition of aspartate aminotransferase (GOT) in human erythrocytes.

The mechanism of acetaldehyde-mediated GOT inhibition was studied in human red cells. In the GOT assay mix, acetaldehyde competitively inhibits activation of apoGOT by pyridoxal phosphate and pyridoxamine phosphate. However, Ki values are 100-1000 times greater than Km values for these B6 vitamers. Moreover, incubation of undiluted lysates with acetaldehyde at 37 degrees inhibits GOT activity without increasing apoGOT levels and without altering affinity of apoGOT for either B6 coenzyme. In undiluted lysates, inhibition is not prevented by disulfiram. However, incubation at 4 degrees prevents both acetaldehyde metabolism and GOT inhibition while preincubation with NaF prevents GOT inhibition without affecting acetaldehyde disappearance. The effect of NaF is completely reversed by pyruvate but only partially reversed by NADH. Glyceraldehyde 3-phosphate, the only glycolytic intermediate which directly inhibits GOT, does not reverse the NaF effect. Thus, inhibition of GOT by acetaldehyde (a) requires nonoxidative metabolism of acetaldehyde and (b) is not mediated either by glycolytic substrates or by impaired binding of B6 vitamers to the GOT apoenzyme. Since NaF had no effect on a lysate deficient in glucose 6-phosphate dehydrogenase, the hexose monophosphate shunt may play a role in acetaldehyde-mediated GOT inhibition.

Acetaldehyde↗
PubMed1989

Loss of proliferative potential during terminal differentiation coincides with the decreased abundance of a subset of heterogeneous ribonuclear proteins.

The decrease in abundance of a subset of highly conserved basic nuclear proteins is established to correlate with the loss of proliferative potential in association with the process of terminal differentiation in murine mesenchymal stem cells and human keratinocytes. These proteins, designated P2Ps for proliferation potential proteins, have apparent molecular masses of 30-40 kD, are associated with the 30-40S substructures of nuclear hnRNP complexes, and are recognized by antibodies made against core proteins of hnRNP particles. They also share an epitope in common with heat shock protein-90 (hsp90) and are recognized by two mAbs against hsp90. Two-dimensional electrophoretic Western blots furthermore show that P2Ps make up a subset of hnRNP proteins. Cells that possess these proteins express the potential to proliferate whether or not they are traversing the cell cycle. These include rapidly growing cells, reversibly growth-arrested cells, and nonterminally differentiated cells. In contrast, cells that have irreversibly lost their proliferative potential, such as terminally differentiated cells, show a marked reduction in the abundance of P2Ps as determined by immunodetection on Western blots. A correlation, therefore, exists between the presence of this subset of nuclear proteins and the proliferative potential in two cell types. These results raise the possibility that as a subset of hnRNP proteins, P2Ps may mediate posttranscriptional control of the processing of specific RNAs required for cell proliferation.

Animals↗
PubMed1989

Erythrocyte O2 transport and metabolism and effects of vitamin B6 therapy in type II diabetes mellitus.

The effects of vitamin B6 on erythrocyte metabolism, erythrocyte hemoglobin O2 affinity (P50), and nonenzymatic glycosylation were studied in 15 Caucasian men with type II (non-insulin-dependent) diabetes mellitus. A control group of 13 healthy Caucasian men was also evaluated. Before treatment, diabetic subjects had low mean cell hemoglobin concentration values and increases in both erythrocyte 2,3-diphosphoglycerate (2,3-DPG) levels and erythrocyte hexokinase activities. Although all three of these changes are associated with a decrease in hemoglobin O2 (Hb-O2) affinity, P50 values were normal in diabetic subjects. Moreover, P50 values normalized to pH 7.4 (P50(7.4] were inversely related to the level of glycosylated hemoglobin (HbA1c). Both erythrocyte 2,3-DPG and erythrocyte ATP were also inversely related to HbA1c. Vitamin B6 nutriture, as determined by erythrocyte aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, was normal in all diabetic subjects before vitamin B6 therapy. Nonetheless, HbA1c levels decreased after 6 wk of treatment with 150 mg/day pyridoxine and increased again during placebo administration. These changes were not explained by changes in fasting blood glucose. Pyridoxine therapy also decreased P50(7.4) values and increased erythrocyte AST and ALT activities but had no effect on 2,3-DPG, ATP, or the activities of hexokinase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase. These observations suggest that 1) nonenzymatic glycosylation may play a role in regulating both erythrocyte metabolism and Hb-O2 affinity in diabetic subjects, and 2) vitamin B6 therapy may modify nonenzymatic glycosylation of hemoglobin in this population.

Animals↗
PubMed1988

Studies on the role of actin's aspartic acid 3 and aspartic acid 11 using oligodeoxynucleotide-directed site-specific mutagenesis.

One or more of the five acidic amino-terminal residues of skeletal muscle actin have been implicated as being important in a number of actin-related processes. We have constructed a series of actins containing mutations at Asp3 and Asp11 and tested these mutant proteins for their ability to bind to DNase I-agarose, polymerize with rabbit skeletal muscle actin, undergo amino-terminal processing, and bind to the myosin-S1 subfragment. The mutant actins were expressed in vitro using a coupled transcription/translation system which involves the synthesis of mutant RNAs with SP6 RNA polymerase followed by their translation in a rabbit reticulocyte lysate. When Asp3 was changed to Ala, His, or Asn there was no difference in the tested properties as compared to wild type actin. These results suggest that an acidic residue at position 3 is not critical for the actin functions measured. When Asp11 was changed to Glu, Asn, or His or if the conserved Asp-Asn sequence at positions 11 and 12 was reversed, the mutants were able to copolymerize with rabbit skeletal muscle actin and be cross-linked to myosin-S1 to nearly the same extent as wild type actin. However, the amount of in vitro-synthesized actin capable of binding to DNase I-agarose with high affinity or undergoing amino-terminal processing was reduced significantly relative to the wild type actin synthesized in vitro. The Asp11 mutants ran anomalously on native polyacrylamide gels suggestive of a conformational change induced in the actin. Together, these results suggest that Asp11 may be important in proper actin folding and function.

Actins↗
PubMed1988

Effects of acetaldehyde on human red cell metabolism: evidence for the formation of enzyme inhibitors.

Since red cells transport and metabolize acetaldehyde in vivo, the effects of acetaldehyde on human red cell enzyme activities were studied. Incubation of intact red cells or undiluted red cell lysates at 37 degrees C for 4 h with 1-10 mmol/l acetaldehyde decreased only GOT, GPT and aldolase activities among the 26 enzymes tested. No inhibition occurred at 4 degrees C or when acetaldehyde was incubated with dilute hemolysates. Incubation of lysates with other reducing substrates or with acetate inhibited aldolase but not GOT or GPT. Preincubation of lysates with cyanate or fluoride markedly decreased acetaldehyde-mediated transaminase inhibition but not aldolase inhibition. Addition of pyridoxal phosphate, the vitamin B6 transaminase coenzyme, to GOT and GPT assay mixes did not reverse acetaldehyde-mediated transaminase inhibition. These findings suggest that acetaldehyde-mediated aldolase inhibition results from oxidation of acetaldehyde while transaminase inhibition results from nonoxidative acetaldehyde metabolism. When 100-200 mumol/l acetaldehyde is added to lysates at 2-h intervals and when lysates are incubated with ethanol, alcohol dehydrogenase and an NAD-regenerating system, enzyme inhibition occurs at acetaldehyde levels approaching those seen in vivo. Thus, the role of acetaldehyde-mediated enzyme inhibition in the toxicity of alcohol abuse warrants further study.

Acetaldehyde↗
PubMed1988

Cyclosporin: pharmacokinetics and detailed studies of plasma and erythrocyte binding during intravenous and oral administration.

On the basis that unbound concentration better correlates with response than total plasma or blood concentration, the inter- and intra-subject variability in the distribution of cyclosporin within blood and to plasma components was studied in renal transplant patients. Pharmacokinetic aspects were also studied. Blood samples were analysed from patients who received the drug both by a 72-h i.v. infusion and orally (7 mg.kg-1 twice daily). Steady-state was reached within 18 h of starting the i.v. infusion; the plasma data were best fitted by a biexponential equation with half-times of 0.13-1.02 h and 4.3-13.9 h, associated with the two phases. The mean plasma clearance was 700 ml/min. Concentrations during the infusions measured by RIA and HPLC were comparable. Oral profiles showed rapid and extensive absorption. The peak plasma concentrations were 1460-1880 micrograms.l-1 and occurred 2-4 h after dosing, with bioavailability estimates of 41-113%. Concentrations measured by RIA were higher than by HPLC. Blood-to-plasma concentration ratio measurements of cyclosporin at 37 degrees C decreased with increasing plasma concentration and increased with haematocrit. Fraction unbound, measured by ultra-centrifugation, was in the range 0.042-0.122 with an average of 0.068, and varied little in some patients but showed systematic changes with time in others. Cyclosporin binding was found to be related not only to the triglyceride but, more particularly, to the cholesterol-related lipoproteins in plasma. Monitoring cholesterol may be helpful in identifying patients with extremes in binding or with widely varying binding.

Administration, Oral↗
PubMed1988

Effect of a meal containing protein on lithium clearance and plasma immunoreactive atrial natriuretic peptide in man.

1. The effect of meals with a high and low protein content and of the fasting state on renal function and plasma atrial natriuretic peptide was studied in water-loaded normal volunteers. 2. Creatinine clearance increased after the high protein meal, but did not change after the low protein meal or while fasting. Observations of similar increases in urine sodium and potassium excretion and a transient decrease in urine flow after both meals suggest that the protein content of the meal is not an important contributory factor in these responses to feeding. 3. Absolute delivery of sodium and water out of the proximal tubules (assessed by the lithium clearance method) was higher after both meals than while fasting; fractional lithium clearance was higher after the low protein meal than the high protein meal and while fasting. Absolute reabsorption from proximal tubules was increased after only the high protein meal. 4. A transient decrease in the fraction of water delivered to distal nephron segments that appeared in the urine (fractional distal water excretion) was observed after both meals. Fractional distal sodium excretion and absolute distal sodium and water reabsorption increased after both meals. 5. Since plasma atrial natriuretic peptide either decreased (high protein meal) or remained unchanged (low protein meal and fasting), it is unlikely that this hormone is involved in the hyperfiltration after the high protein meal and the natriuresis after both high and low protein meals.

Adult↗
PubMed1988

Effect of low dose infusion of atrial natriuretic peptide on renal function in man.

1. The effects of the infusion of a low dose (2 pmol min-1 kg-1 for 3 h) of human atrial natriuretic peptide (hANP) were studied in seven healthy volunteers undergoing a water diuresis. Lithium clearance was used to monitor proximal tubular function. 2. hANP increased urine flow rate, sodium, calcium and magnesium excretion without significant changes in potassium and phosphate excretion, heart rate or blood pressure. 3. hANP caused a small change in fractional lithium clearance, and larger changes in distal nephron handling of sodium and water. 4. Plasma renin activity tended to decrease during the infusion of hANP, while plasma aldosterone concentration decreased during and increased after stopping the infusion of hANP. 5. The data suggest that hANP inhibits the reabsorption of sodium and water by an action on distal segments of the nephron and perhaps the proximal tubule. Inhibition of renin and aldosterone secretion may contribute to the natriuresis.

Adult↗
PubMed1988

Rheumatoid disease presenting as a nephrotic syndrome.

A 62 year old man with no relevant previous history presented with a nephrotic syndrome. Renal biopsy showed a membranous glomerulopathy and coincident investigation showed high serum titres of rheumatoid factors. It was not until some months later that he developed articular and extra-articular manifestations of rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed1988

Prospective controlled study of androgen therapy in the anemia of chronic renal disease: effects on iron kinetics.

Ferrokinetic and RBC mass determinations were made at 3-month intervals in iron-replete hemodialysis patients randomized to a control group or to nandrolone decanoate therapy. After 3 months, RBC mass increased in two of 4 androgen-treated patients. Erythron iron turnover, an index of RBC production, increased in the one responder studied but not in the two nonresponders. Similarly, in a fifth subject, who was not restudied until 6 months of androgen therapy were completed, an increase in RBC mass was associated with an increase in erythron iron turnover. However, between 3 and 6 months, RBC mass increased in all 4 androgen-treated patients studied even though erythron iron turnovers remained unchanged and dialysis-associated blood losses did not decrease. Thus, at least two androgen-treated patients had increases in RBC mass without ever increasing their erythron iron turnover. Two of three control subjects also had increased erythron iron turnovers, which in one case was related to increased dialysis-associated blood losses. Changes in RBC mass were not consistently paralleled by changes in Hb. These findings suggest that increases in RBC mass during nandrolone decanoate therapy result from two mechanisms: increased erythropoiesis (shown by simultaneous increases in RBC mass and erythron iron turnover) and increased RBC survival (indirectly shown by increases in RBC mass without increases in erythron iron turnover). The importance of control groups, RBC mass determinations and the monitoring of dialysis-associated blood losses in studying the effects of androgens on erythropoiesis in chronic hemodialysis patients is also demonstrated.

Anemia↗
PubMed1987

Studies on the mechanism of acetaldehyde-mediated inhibition of rat liver transaminases.

Incubation of mitochondria-depleted rat liver homogenates with 5 mmol/l acetaldehyde at 37 degrees C for 1 h inhibited both aspartate and alanine aminotransferases by 30%. Inhibition was prevented by decreasing temperature to 4 degrees C or by preincubating homogenates with cyanate but was unaffected by cyanamide and methylpyrazole which block acetaldehyde oxidation and reduction respectively. Cyanate-sensitive acetaldehyde-mediated inhibition of purified porcine heart transaminases was also demonstrated in the presence of rat liver homogenate but not in Tris/sucrose medium. Moreover, porcine transaminases were inhibited by trichloroacetic acid extracts of rat liver homogenates previously incubated with acetaldehyde but not by extracts of homogenates incubated with both acetaldehyde and cyanate. These findings suggest that acetaldehyde-mediated transaminase inhibition requires further non-oxidative metabolism of acetaldehyde. Since transaminase activities were not restored by addition of pyridoxal 5'-phosphate to the assay systems, acetaldehyde-induced transaminase inhibition does not appear to be mediated by displacement or depletion of this B6 coenzyme.

Acetaldehyde↗
PubMed1987

Studies on the role of actin's N tau-methylhistidine using oligodeoxynucleotide-directed site-specific mutagenesis.

The primary structure of all actins except that isolated from Naegleria gruberi contains a unique N tau-methylhistidine (MeHis) at position 73. This modified residue has been implicated as possibly being important for the post-translational processing of actin's amino terminus, the binding of actin to DNase I, and in the polymerization of G-actin. We have investigated the potential role of MeHis in each of these processes by utilizing site-directed mutagenesis to change His-73 of skeletal muscle actin to Arg and Tyr. Wild type and mutant actins were synthesized in vivo, using non-muscle cells transfected with mutant cDNAs, and in vitro by translating mutant RNAs synthesized using SP6 RNA polymerase in a rabbit reticulocyte lysate. We have found that actins containing Arg or Tyr at position 73 undergo amino-terminal processing, bind to DNase I-agarose, and become incorporated into the cytoskeleton of a nonmuscle cell as efficiently as wild type actin. Furthermore, using an in vitro copolymerization assay we have found that although there is no difference between the Arg mutant and the wild type actins, the Tyr mutant has a slightly greater critical concentration for polymerization. These results show that MeHis is not absolutely required for any of these processes.

Actins↗
PubMed1987

Evidence for the generation of transaminase inhibitor(s) during ethanol metabolism by rat liver homogenates: a potential mechanism for alcohol toxicity.

Since ethanol consumption decreases hepatic aminotransferase activities in vivo, mechanisms of ethanol-mediated transaminase inhibition were explored in vitro using mitochondria-depleted rat liver homogenates. When homogenates were incubated at 37 degrees with 50 mM ethanol for 1 hr, alanine aminotransferase decreased by 20%, while aspartate aminotransferase was unchanged. After 2 hr, aspartate aminotransferase decreased by 20% and by 3 hr, alanine and aspartate aminotransferases were decreased by 31 and 23%, respectively. Levels of acetaldehyde generated during ethanol oxidation were 525 +/- 47 microM at 1 hr, 855 +/- 14 microM at 2 hr, and 1293 +/- 140 microM at 3 hr. Although inhibition of alcohol oxidation with methylpyrazole or cyanide markedly decreased ethanol-mediated transaminase inhibition, neither incubation with acetate nor generation of reducing equivalents by oxidation of lactate, malate, xylitol, or sorbitol altered the activity of either enzyme. However, semicarbazide, an aldehyde scavenger, prevented inhibition of both aminotransferases by ethanol. Moreover, incubation with 5 mM acetaldehyde for 1 hr inhibited alanine and aspartate aminotransferases by 36 and 26%, respectively. Cyanamide, an aldehyde dehydrogenase inhibitor, had little effect on ethanol-mediated transaminase inhibition. Thus, metabolism of ethanol by rat liver homogenates produces transaminase inhibition similar to that described in vivo and this effect requires acetaldehyde generation but not acetaldehyde oxidation. Since addition of pyridoxal 5'-phosphate to assay mixes did not reverse ethanol effects, aminotransferase inhibition does not result from displacement of vitamin B6 coenzymes.

Acetaldehyde↗
PubMed1987

Effect of dietary sodium chloride and posture on plasma immunoreactive atrial natriuretic peptide concentrations in man.

The effect of changes of dietary sodium chloride intake and posture on plasma atrial natriuretic peptide concentration and renal function was studied in 11 normal human volunteers. Plasma atrial natriuretic peptide concentration was higher in the upright posture on a high than it was on a medium or low salt diet. On the medium and high but not on the low salt diet the concentration increased significantly on adoption of the supine posture. Creatinine, sodium, lithium and fractional lithium clearances, fractional distal sodium excretion and total distal water and sodium reabsorption, which were estimated by the lithium clearance technique, were significantly higher on the high than on the low salt diet. The medium salt intake gave intermediate values. Heart rate while upright was significantly higher on the low than on either the medium or the high salt diets. Systolic blood pressure was unaffected by salt intake. Diastolic blood pressure in the supine position was significantly higher on the low than on the medium or high salt diets. Both plasma noradrenaline concentrations and plasma renin activity were significantly higher on the low than on the high salt diet. Values on the medium salt intake were intermediate. Plasma concentrations of both hormones were higher in the upright than in the supine posture on all three salt intakes. The data are consistent with the hypothesis that atrial natriuretic peptide contributes to the cardiovascular and renal adjustments to changes in dietary sodium chloride, and the possible role of the peptide is discussed.

Adult↗
PubMed1987

Lithium clearance in man: effects of dietary salt intake, acute changes in extracellular fluid volume, amiloride and frusemide.

1. The effects of amiloride and frusemide on lithium clearance were studied during changes in dietary sodium chloride intake and during infusion of 0.9% NaCl in normal human volunteers. 2. Lithium and fractional lithium clearances were less on the low than on the high salt diet. Values for the medium salt diet were intermediate. Acute extracellular fluid volume expansion with 0.9% NaCl infusion and extracellular fluid volume contraction 3-4 h after intravenous frusemide caused lithium and fractional lithium clearances to increase and decrease respectively. 3. Amiloride caused small changes in lithium and fractional lithium clearances on a low salt diet, but was without effect when salt intake was medium or high. 4. Increases in lithium clearance occurred immediately after frusemide irrespective of dietary salt intake and in subjects infused with 0.9% NaCl. Only in salt-depleted subjects did frusemide cause a substantial increase in fractional lithium clearance. Changes induced under other circumstances were small. 5. It is concluded that the lithium clearance method for assessment of proximal tubule salt and water reabsorption can be used with some degree of confidence in certain circumstances (medium and high salt intake as well as in acute volume expansion) but may not be reliable when dietary salt intake is low.

Adult↗
PubMed1987

Pharmacokinetics of cyclosporin: influence of rate of constant intravenous infusion in renal transplant patients.

1 The pharmacokinetics of cyclosporin were studied in 12 renal transplant patients. Five patients received a constant rate (7 mg kg-1 day-1) intravenous infusion over 72 h and the remainder received rates of 7, 4 and 10 mg kg-1 day-1, consecutively each for at least 24 h. 2 Plasma, separated at 37 degrees C, was analysed by h.p.l.c. 3 The data were best described by a biexponential model. 4 Following the 72 h infusion, a plateau was reached by 24 h and clearance was 0.60 l h-1 kg-1. 5 Clearance associated with the 10 mg kg-1 day-1 infusion rate (0.43 l h-1 kg-1) was estimated to be lower than that following the 4 and 7 mg kg-1 day-1 rates (0.52 and 0.54 l h-1 kg-1 respectively) but the difference is unlikely to be of clinical significance.

Adult↗