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At least 19 recordsLinked to original sources
PubMed1975

Studies on thyroid hormone-binding proteins. II. Binding of thyroid hormones, retinol-binding protein, and fluorescent probes to prealbumin and effects of thyroxine on prealbumin subunit self association.

Vitamin A in human plasma is transported by its specific carrier protein, the retinol-binding protein. Under physiological conditions the protein forms a stable protein-protein complex with the tetrameric plasma protein, the thyroxine-binding prealbumin. Human prealbumin was shown to interact with the fluorescent probes 1,8-anilinonaphthalene sulfonate (ANS) and 2-p-toluidinylnaphthalene-6-sulfonate (TNS). ANS bound to the protein at two independent sites with the apparent association constant 3 X 10(5) M-1, whereas TNS interacted with a single site with the binding constant 5 X 10(k) M-1. The fluorescent yield of protein-bound ANS was 0.95, a more than 200-fold enhancement compared with that of ANS in aqueous solutions. TNS enhanced its quantum yield nearly 500-fold to 0.37. On addition of thyroid hormones the fluorescent probes could be quantitatively displaced from the protein. This finding suggested that triiodthyronine, thyroxine, and the probes bound to a common site in prealbumin, which is likely to have a strongly hydrophobic character. The association constants for the interaction between prealbumin and the thyroid hormones could be calculated by using the hormones as competitive inhibitors in the TNS-prealbumin titrations. The data from the competition experiments together with those obtained from equilibrium dialysis revealed one major hormone binding site on the protein. The calculated association constant were 9 X 10(6) M-1 and 1 X 10(8) M-1 for triiodothyronine and thyroxine, respectively. Prealbumin monomers were bound to Sepharose by covalent attachment, and their properties were examined. Evidence was obtained demonstrating that the retinol-binding protein could interact with a single subunit of prealbumin. The estimated apparent association constant for the interaction of the protein and the matrix-bound monomeric prealbumin was 3 X 10(4) M-1, approximately 250-fold lower than that measured for protein and matrix-bound tetrameric prealbumin. The data, however, strongly suggest that there are four retinol-binding protein sites per prealbumin molecule. Using the technique of sedimentation equilibrium ultracentrifugation the prealbumin subunit self-association has been studied. The energy of the interaction for the prealbumin subunits is very high, and various concentrations of guanidine hydrochloride has to be used to perturb the equilibrium. All experiments indicated that prealbumin dissociates directly into monomers without the presence of intermediate forms. Thyroxine perturbed the chemical equilibrium of the prealbumin monomer-tetramer system by strengthening the interaction between the subunits.

Anilino Naphthalenesulfonates↗
PubMed1985

Serum prealbumin and retinol-binding protein in the prealbumin-related senile and familial forms of systemic amyloidosis.

In a series of 13 elderly patients with proven prealbumin-related senile systemic amyloidosis (SSA), depressed serum prealbumin values (110.7 +/- 14.1 micrograms/ml) were found as compared to an age-matched control group (175.1 +/- 20.3 micrograms/ml). As expected, there was a significant correlation between serum prealbumin and serum retinol-binding proteins in both groups of patients. Patients with reactive amyloid protein AA amyloidosis had slightly depressed serum prealbumin concentrations, whereas patients with prealbumin-related familial amyloidosis of Swedish type had prealbumin values within normal limits. Since the serum levels of the acute phase reactants, haptoglobin and amyloid-related serum protein AA, were higher in the group of patients with reactive amyloidosis than in patients with SSA, the depression of the prealbumin levels in SSA is not a result of inflammation. Since SSA is known to contain prealbumin, it is possible that a disturbed prealbumin metabolism in old age results in low prealbumin serum values and deposition of amyloid.

Adult↗
PubMed1985

The primary structure of rabbit and rat prealbumin and a comparison with the tertiary structure of human prealbumin.

The primary structures of rabbit and rat prealbumin have been determined. The amino acid sequence of rabbit prealbumin was determined by analyses of peptides obtained by trypsin and Staphylococcus aureus protease digestions. The rat prealbumin sequence was deduced by analyses of tryptic peptides as well as by nucleotide sequencing of cDNA clones. Both amino acid sequences contain 127 amino acid residues, the same as human prealbumin. Pairwise comparisons show that the three sequences are more than 80% identical. All three prealbumins were found to display significant sequence homology with human thyroxine-binding globulin. A comparison of the primary structures of the prealbumins with the tertiary structure of human prealbumin shows that amino acid replacements are preferentially located at the surface of the molecule and in the loops connecting the beta-strands. The locations of the replacements are discussed as regards the different molecular interactions in which prealbumin is involved.

Amino Acid Sequence↗
PubMed1989

Role of variant prealbumin in the pathogenesis of familial amyloidotic polyneuropathy: fate of normal and variant prealbumin in the circulation.

According to recent studies on protein chemistry and genetic engineering, replacement of the Val30 residue of prealbumin by methionine is believed to play a critical role in the formation of amyloid deposit and the pathogenesis of familial amyloidotic polyneuropathy (FAP). However, only limited information is available concerning the behavior of prealbumin in the circulation. To obtain the molecular insight into the mechanism of amyloid deposition, it is indispensable to know the fates of normal and variant prealbumin in vivo. Thus, the fates of prealbumin samples from normal and FAP patients were studied in normal rats as well as in animals that were challenged with acute inflammation induced by turpentine. The effect of in vitro photooxidation of prealbumin samples on their behavior was also examined in vivo. Kinetic analysis revealed no appreciable difference between prealbumin samples from normal and FAP patients. These results suggest that factors other than the rate of transfer of the variant form prealbumin from plasma to an extravascular compartment may play a critical role in the pathogenesis of amyloid deposition in FAP patients.

Amyloidosis↗
PubMed1984

Cloning of human prealbumin complementary DNA. Localization of the gene to chromosome 18 and detection of a variant prealbumin allele in a family with familial amyloid polyneuropathy.

Prealbumin, a 55,000 Mr protein, is a normal constituent of human serum. In patients with familial amyloid polyneuropathy (FAP), an autosomal dominant disease, variant prealbumin molecules are found in association with systemic amyloid deposits. One variant prealbumin has a methionine for valine substitution at amino acid 30 and has been implicated in the pathogenesis of type 1 FAP. A prealbumin-specific complementary DNA clone has been isolated from an adult human liver library and used in Southern blot hybridization experiments to identify a unique NsiI restriction endonuclease site in the variant allele carried by type 1 FAP patients with the methionine for valine substitution. The complementary DNA clone has been used to analyse a panel of human-mouse and human--hamster somatic cell hybrid DNAs and localize the prealbumin gene to chromosome 18.

Alleles↗
PubMed2001

Serial prealbumin levels as predictors of outcomes in a retrospective cohort of peritoneal and hemodialysis patients.

OBJECTIVE: Although earlier research has suggested that baseline prealbumin level is an independent predictor of outcome among dialysis patients, the prognostic importance of serial prealbumin levels is less clear. The present study had 3 objectives: first, to determine if prealbumin (a marker of visceral protein stores with a relatively short half-life) predicts subsequent albumin levels taken at least 1 month later; second, to examine the association between serial prealbumin levels and clinical outcome; and third, to examine the association between changes in prealbumin level and outcome. DESIGN: The prognostic value of serial prealbumin levels was examined by linear regression analysis and Cox hazard models in an observational cohort study using a repeated measures design and time-dependent covariates. SETTING: Patients were followed by a tertiary care center, receiving hemodialysis (HD; at either an in-center dialysis unit or one of several satellite units operated by the hospital) or home peritoneal dialysis (PD). PATIENTS: A retrospective cohort was identified consisting of 268 incident and prevalent chronic HD and PD patients receiving dialysis from June 1998 to September 1999. MAIN OUTCOME: The study examined the association between serial prealbumin measurements and future laboratory and clinical outcomes (albumin, hospitalization, and death). RESULTS: Serial prealbumin values were independent predictors of future albumin levels among HD patients (P =.04), but not PD patients. Independent predictors of hospitalization included diabetes for PD patients (P =.0012) and advanced age for HD patients (P =.0008). Advanced age and diabetes were independent predictors of death for both HD (P =.0001 and P =.0368) and PD patients (P =.0014 and P =.0164). Serial prealbumin values, measured as time-dependent covariates, did not predict hospitalization or death. Further analyses examined the prognostic value of changes in prealbumin and albumin values as time-dependent covariates. The final multivariate analysis identified low baseline albumin level as an independent predictor of hospitalization among HD patients (P =.0282), whereas low baseline prealbumin was an independent predictor of death for HD patients (P =.0001). Interestingly, negative changes in serial prealbumin measurements were also independent predictors of death among HD patients (P =.0025). CONCLUSION: Serial prealbumin measurements predict subsequent albumin values among HD patients. As well, low baseline prealbumin level is an independent predictor of adverse outcome among HD patients. Although repeated prealbumin measurements in and of themselves were of no added prognostic value, falling prealbumin values identified by repeated measurements were additional independent predictors of death. These results support the clinical utility of regular prealbumin monitoring among HD patients.

Biomarkers↗
PubMed2005

Prealbumin, mortality, and cause-specific hospitalization in hemodialysis patients.

BACKGROUND: Prealbumin (transthyretin) is a hepatic secretory protein thought to be important in the evaluation of nutritional deficiency and nutrition support. Prior studies have suggested that the serum prealbumin concentration is independently associated with mortality in hemodialysis patients, even with adjustment for serum albumin and other nutritional parameters. METHODS: To determine whether prealbumin was independently associated with mortality and morbidity (cause-specific hospitalization) in hemodialysis patients, we analyzed data on 7815 hemodialysis patients with at least one determination of serum prealbumin during the last three months of 1997. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum prealbumin using proportional hazards regression. We also determined whether the prealbumin concentration was associated with all-cause, cardiovascular, infection-related, and vascular access-related hospitalization. RESULTS: The relative risk (RR) of death was inversely related to the serum prealbumin concentration. Relative to prealbumin > or =40 mg/dL, the adjusted RRs of death were 2.41, 1.85, 1.49, and 1.23 for prealbumin <15, 15-20, 20-25, and 25-30 mg/dL, respectively. The adjusted RRs of hospitalization due to infection were 2.97, 1.95, 1.81, and 1.61 for prealbumin <15, 15-20, 20-25, and 25-30 mg/dL, respectively. The adjusted RRs of vascular access-related hospitalization were 0.48, 0.52, 0.58, and 0.71 for prealbumin <15, 15-20, 20-25, and 25-30 mg/dL, respectively. While serum albumin was strongly associated with mortality and all-cause hospitalization, it was not associated with hospitalization due to infection, and lower levels were associated with higher rather than lower rates of vascular access-related hospitalization. CONCLUSION: In hemodialysis patients, lower prealbumin concentrations were associated with mortality and hospitalization due to infection, independent of serum albumin and other clinical characteristics. Higher prealbumin concentrations were associated with vascular access-related hospitalization. In light of these findings, more intensive study into the determinants and biological actions of prealbumin (transthyretin) in end-stage renal disease is warranted.

Aged↗
PubMed1982

Metabolism of prealbumin in rats and changes induced by acute inflammation.

Prealbumin was purified from rat plasma by chromatography on Blue Sepharose CL-6B, followed by chromatography on concanavalin-A--Sepharose and preparative electrophoresis in polyacrylamide gel. The overall recovery was 20%. The purified prealbumin was homogeneous upon electrophoresis in detergent containing polyacrylamide gel and was used to raise a monospecific anti-serum in rabbits. During perfusion of rat liver, [14C]-leucine was incorporated into prealbumin secreted into the perfusion medium, suggesting that the liver was synthesizing prealbumin. The ratio of the rate of incorporation of leucine into prealbumin to that into total protein was 1.5%. 125I-prealbumin had a half-life of 29 h in the bloodstream of healthy Buffalo rats on a diet containing 20% protein. Whole body homogenates from healthy rats contained 6.2 mg prealbumin/100 g body weight. The rate of synthesis of prealbumin, calculated from half-life and total body pool, was 3.6 mg prealbumin X (100 g body weight)-1 X day-1. Two days after induction of inflammation by a subcutaneous injection of turpentine, both the concentration of prealbumin in the plasma and the amount of prealbumin in the whole body homogenates decreased to a minimum of about one third of normal. The relative rate of degradation of 125I-prealbumin did not change during inflammation. The rate of synthesis of prealbumin decreased considerably, or even ceased, during acute inflammation.

Acute Disease↗
PubMed2000

Prealbumin is as important as albumin in the nutritional assessment of hemodialysis patients.

BACKGROUND: Although serum prealbumin is considered a valid indicator of nutritional status in hemodialysis patients, there is relatively little evidence that its determination is of major prognostic significance. In this study, we aimed to determine the independent association of serum prealbumin with survival in hemodialysis patients, after adjusting for serum albumin and other indicators of protein energy nutritional status. METHODS: Serum prealbumin was measured in more than 1600 maintenance hemodialysis patients. We determined the correlations among prealbumin and other indicators of nutritional status, including serum albumin, and bioimpedance-derived indicators of body composition. The relationship between serum prealbumin and survival was determined using proportional hazards regression. RESULTS: The serum albumin was directly correlated with the serum prealbumin (r = 0.47, P < 0.0001), but still explained <25% of the variability in prealbumin. Prealbumin was inversely related to mortality, with a relative risk reduction of 6% per 1 mg/dL increase in prealbumin, even after adjusting for case mix, serum albumin, and other nutritional indicators. The increase in risk with lower serum prealbumin concentrations was observed whether the serum albumin was high or low. CONCLUSION: In hemodialysis patients, the serum prealbumin provides prognostic value independent of the serum albumin and other established predictors of mortality in this population.

Aged↗
PubMed1986

Effect of gestational age upon prealbumin and retinol binding protein in preterm and term infants.

The relationships between maternal and umbilical cord levels of prealbumin and retinol binding protein (RBP) were studied in 68 mothers and in their appropriate-for-gestational-age neonates delivered between 25 and 42 weeks gestation. Arterial and venous concentrations of prealbumin and RBP in cord sera were also studied in a subsample of eight infants. In cord sera, prealbumin and RBP levels increased with gestational age (prealbumin, r = 0.47; RBP, r = 0.40, p less than 0.01), and were significantly different in neonates born at term compared to those born prematurely (mean +/- SD, prealbumin 12.0 +/- 3.9 mg/dl vs. 8.8 +/- 2.3 mg/dl, p less than 0.001; RBP, 2.3 +/- 0.8 vs. 1.8 +/- 0.5 mg/dl, p less than 0.005). No significant differences between arterial and venous concentrations of prealbumin and RBP were observed in cord blood. In maternal blood, serum prealbumin and RBP concentrations did not increase with length of gestation (25-42 weeks). Maternal prealbumin was not correlated significantly with infants' cord serum levels; the correlation coefficient for RBP was 0.29, p less than 0.05. Maternal prealbumin and RBP serum levels were approximately twice the values seen in neonates born both at term and prematurely. Although the difference between premature and full-term cord levels of prealbumin and RBP may reflect an increase in hepatic protein synthesis that occurs with maturation of the fetus and/or a change in placental function after 37 weeks gestation, neither of these factors sufficiently explains the variance in neonatal prealbumin and RBP levels.

Female↗
PubMed1994

Plasma prealbumin in women with epithelial ovarian carcinoma.

BACKGROUND: Epithelial ovarian carcinoma produces steroid hormones that may be of prognostic importance. The steroids are mainly bound to plasma albumin and sex hormone-binding globulin. Alterations in plasma protein levels influence hormonal effects. As plasma prealbumin may reflect changes in the patient's clinical status better than do albumin determinations, it is of interest to analyze prealbumin in patients with ovarian cancer. METHODS: Fifty-one postmenopausal or oophorectomized women with epithelial cancer of the ovary were studied. Plasma prealbumin was analyzed prior to and during chemotherapy. Tumor volumes were evaluated and blood samples were drawn for prealbumin analysis on four occasions at monthly intervals. Plasma levels were compared with one control group of postmenopausal women, one group of fertile women in the follicular phase of the menstrual cycle, and one control group of postmenopausal women with nongynecologic disseminated malignant disease. RESULTS: Prealbumin concentrations are lower in women with carcinoma of the ovary than in postmenopausal controls and the levels correlate inversely to tumor volume. Prealbumin concentrations are decreased in the large tumor group, advanced tumor stage group and in the control group with nongynecologic disseminated malignant disease. During chemotherapy, plasma prealbumin increases concomitantly with the reduction of tumor volume. Initial plasma prealbumin concentration seems to have prognostic importance. CONCLUSIONS: Prealbumin may be a sensitive indicator of disturbances in protein metabolism. It may reflect changes in the patient's clinical status better than do albumin determinations. Prealbumin concentration seems to have a prognostic importance in women with epithelial ovarian carcinoma. CONDENSATION: Prealbumin is studied in women with epithelial ovarian carcinoma prior to and during chemotherapy, and is found to vary inversely with changes in tumor volume.

Adult↗
PubMed1985

Transport of thyroxine bound to human prealbumin into rat liver.

The transport into rat liver of thyroxine (T4) bound to human prealbumin was studied with the use of sera obtained from patients with thyroid hormone-binding globulin (TBG) deficiency and with purified human prealbumin. The unidirectional extraction of 125I-T4 by liver was measured after rapid injection of isotope mixed in human serum into the portal vein of ketamine-anesthetized rats. The percentage of total serum T4 transported into liver was 47.6 +/- 5.2% in subjects with TBG deficiency, and this represented a 50% increase in hepatic T4 transport relative to control human serum. Since T4 is bound to albumin and to prealbumin in complete TBG deficiency, these results suggested that T4 bound to human prealbumin was transported into rat liver. This was confirmed using portal vein injections of human prealbumin at physiological concentrations (0.1-0.3 mg/ml). At these concentrations, T4 bound to human prealbumin was readily transported into liver. These studies suggest factors present in the liver microcirculation inhibit the binding of T4 to human prealbumin such that T4 bound to human prealbumin is highly transportable in liver; conversely, T4 bound to rat prealbumin is not transportable in rat liver. The inability of human prealbumin to sequester T4 in plasma may provide the basis for the selective advantage in humans of TBG, which does sequester T4 in plasma.

Adult↗
PubMed1986

Analyses of prealbumin mRNAs in individuals with familial amyloidotic polyneuropathy.

The distribution of prealbumin mRNA in various tissues of a control subject and an individual with familial amyloidotic polyneuropathy (FAP) was investigated using a cloned human prealbumin cDNA as a probe. Prealbumin mRNAs were detected in the total RNAs from liver and choroid plexus of brain, but not in those from brain, heart, kidney, and thyroid gland. The level of prealbumin mRNA in the choroid plexus was about 100-fold higher than that in the liver. We detected no differences in the sizes of prealbumin mRNAs in the liver and choroid plexus of the control subject, or in those of the individual with FAP, and found that the prealbumin mRNAs in these tissues had been transcribed from a common transcription initiation site. The levels of prealbumin mRNAs in the livers of four control subjects and those of six individuals with FAP were much the same. Because all the individuals with FAP so far examined were heterozygous for the prealbumin gene, carrying one normal and one mutant gene, the levels of the normal and mutant prealbumin mRNAs in the liver and the brain tissue containing choroid plexus were separately estimated and were found to be approximately equal.

Amyloidosis↗
PubMed1984

A prealbumin variant with an increased affinity for T4 and reverse-T3.

A euthyroid adult female (LC) was found to have persistently raised concentrations of total T4 (159 nmol/l) and rT3 (500 pmol/l) in her serum in association with a normal T3 (2.1 nmol/l). Serum concentrations of all three T4-binding proteins were within normal limits. A variant prealbumin with an increased affinity for T4 was found to be responsible for the raised serum level of T4. Unlike normal prealbumin, the variant also bound appreciable amounts of rT3. The affinity constant for T4 binding to prealbumin LC was 5.5 X 10(8) l/mole which is sevenfold higher than that obtained for normal prealbumin (8.5 X 10(7) l/mole). The affinity constant for the binding of rT3 to prealbumin LC was 2.0 X 10(6) l/mole while that for the normal protein was unmeasurable by our method. The T4-binding capacity of prealbumin LC in serum was within the normal range indicating that there is no new additional T4-binding site on the protein. Prealbumin LC has the same molecular size as the normal protein, hence it is likely that the tetrameric structure has been preserved. The electrophoretic mobility of prealbumin LC was normal indicating no alteration in charge. It is postulated that the increased affinity for T4 (and presumably for rT3) results from a hydrophobic amino-acid substitution in the prealbumin monomer.

Adult↗
PubMed1982

Photoaffinity labeling of human thyroxine-binding prealbumin with thyroxine and N-(ethyl-2-diazomalonyl)thyroxine.

To facilitate studies of thyroid hormone-binding proteins, we have synthesized and tested the photoaffinity analogues N-(ethyl-2-diazomalonyl)-3,5,3'-triiodothyronine (EDM-T3) and N-(ethyl-2-diazomalonyl)thyroxine (EDM-T4). The binding affinities of L-EDM-T4 and D-EDM-T4 to human thyroxine-binding prealbumin were 4% and 13.2%, respectively, that of L-thyroxine (L-T4). For comparison the affinities of L-EDM-T3 and D-EDM-T3 to crude rate liver nuclear receptor preparation were 0.1% and 0.7%, respectively, that of L-triiodothyronine (L-T3). Photolysis of prealbumin-[125I]-L-EDM-T4 complexes at 254 nm resulted in covalent linkage of [125I]-L-EDM-T4 to prealbumin as judged by sodium dodecyl sulfate gel electrophoresis. Virtually no labeling was observed in the absence of photolysis. Photolabeling of prealbumin was specific for the high-affinity hormone binding site since it was (a) completely blocked during photolysis in the presence of excess 3,5,3',5'-tetraiodothyroacetic acid, (b) saturated at high [125I]-L-EDM-T4 concentrations, (c) prevented when the hormone binding site had been previously blocked by dansylation of prealbumin, and (d) blocked competitively by T3 and T4 with inhibition constants (K1) similar to the dissociation constants (Kd) for these ligands. Analysis of prealbumin photolabeling by direct attachment of [125I]-L-EDM-T4 or attachment of unlabeled L-EDM-T4 followed by titration of the remaining sites with [125I]-L-T4 indicated a photolabeling efficiency of 54-61% at 63-67% site occupancy. After destruction of the diazo group by preirradiation, L-EDM-T4 was found to label prealbumin after further irradiation; 19-26% photolabeling efficiency could be achieved by using preirradiated reagent at 87-91% site occupancy. This carbene-independent photoattachment was also specific for a high-affinity hormone binding site. The mechanism of the carbene-independent process may involve attachment via radical formation following photoinduced loss of the thyronine ring iodine. Accordingly, specific covalent cross-linking of L-T4 to prealbumin was demonstrated; however, the photolabeling efficiency was much lower than that with preirradiated EDM-T4. Both EDM-T4 and T4 were employed to photolabel prealbumin, thyroxine binding globulin, and albumin in unfractionated human serum.

Affinity Labels↗
PubMed1986

Identification of carriers of mutant prealbumin gene associated with familial amyloidotic polyneuropathy type I by Southern blot procedures: study of six pedigrees in the Arao district of Japan.

Fifty-six Japanese individuals from six pedigrees with familial amyloidotic polyneuropathy (FAP), together with 2 individuals with symptomatic FAP from an unknown pedigree were analyzed, using the Southern blot procedures for the prealbumin gene structure. A human prealbumin cDNA was used as the probe. Altogether, these individuals included 20 with symptomatic FAP, 30 who were asymptomatic, and 8 disease-free spouses. Twenty individuals with symptomatic FAP were all heterozygous for the prealbumin genes, carrying one normal and one mutant gene. We confirmed the direct linkage between the mutant prealbumin gene and the Japanese type of FAP. Moreover, 10 of the 30 asymptomatic individuals from pedigrees with FAP were also heterozygous for the prealbumin gene. The number of asymptomatic individuals with the mutant prealbumin gene showed age-related decreases, and none was over 40 years. A linkage between the mutant prealbumin gene and serum levels of the prealbumin variant was also evident.

Adolescent↗