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At least 19 recordsLinked to original sources
PubMed1978

Depletion of serum hemopexin in fulminant rhabdomyolysis. Evidence for an interaction of hemopexin with myoglobin-derived heme.

Hemopexin is a normal serum glycoprotein that functions as a carrier for intravascularly liberated free heme. Although its role is well established in the reutilization of hemoglobin-derived heme, there have been no previous clinical data to support its suspected interaction with heme released in the degradation of myoglobin. In a patient with fulminant rhabdomyolysis, we found depletion of serum hemopexin in the presence of high serum levels of myoglobin with normal levels of haptoglobin and hemoglobin. This combination of laboratory findings is evidence for an interaction between myoglobin-derived heme and hemopexin and implies a role for hemopexin in the catabolism of myoglobin. These findings support the proposed induction mechanism for observed increases of serum hemopexin in Duchenne muscular dystrophy and in polymyositis.

Acute Disease↗
PubMed1976

Catabolism of homologous and heterologous hemopexin in the rat and uptake of hemopexin by isolated perfused rat liver.

Iodinated hemopexin (Hx) from three different species, rabbit, human and rat, was injected into rats and its clearance from the plasma measured. Rabbit, human and rat apo-Hx were cleared from the plasma with a T 1/2 of 20--31 h, 31--32 h, and 48--60 h respectively. Heme injection (10 mg/kg) after equilibration of the protein immediately accelerates elimination of the hemopexins of all three species (T 1/2 of 4.5 to 10 h). This indicates that the two heterologous hemopexins maintain their function in heme transport. The T 1/2 of rabbit and human Hx return to pre-heme injection values 16 to 20 hours after the injection of heme. For rat Hx, however, the T 1/2, which was 54 +/- 3.5 h before heme injection, was reduced to 25 +/- 1.3 h 20 hours after heme injection. Administration of 1.2--1.3 mg of protoporphyrin IX or uroporphyrin III, after equilibration of iodinated rat Hx, did not change the T 1/2 of the protein, whereas the same amount of coproporphyrin III significantly reduced its T 1/2 from 54 +/- 3.5 to 37 +/- 0.4 h. In addition, the uptake of rat apo-Hx, heme-Hx and albumin by rat liver tissue was measured in an isolated liver perfusion system using radioiodinated proteins screened in vivo. The uptake of apo-Hx by the liver after 2 h (46.8 ml/100 g) was less than that of heme-Hx (67.3 ml/100 g). The amount of apo-Hx and heme-Hx associated with the liver, relative to that circulating in the perfusate, was greater than that of albumin (12.1 ml/100 g). These results are considered to represent selective uptake of Hx by the liver induced by its interaction with heme.

Animals↗
PubMed1976

The aromatic and heme chromophores of rabbit hemopexin. Difference absorption and fluorescence spectra.

Spectrophotometric and fluorimetric techniques were employed to charcterize the environment of the heme chromophore of rabbit hemopexin and to monitor changes in the environment of aromatic amino acid residues induced by the interaction of hemopexin with porphyrins and metalloporphyrins. Difference spectra showed maxima at 292 and 285 nm when hemopexin binds heme or deuteroheme but not deuteroporphyrin. These maxima are attributed to alterations in the local environment of tryptophan and tyrosine residues. Spectro-photometric titrations of the tyrosine residues of hemopexin, heme-hemopexin and hemopexin in 8 M urea showed apparent pK values at 11.4, 11.7, and 10.9 respectively. Perturbation difference spectra produced by 20% v/v ethylene glycol are consistent with the exposure of 6-8 of the 14 tyrosine residues and 6-8 of the 15 tryptophan residues of rabbit hemopexin to this perturbant. Only small differences were found between the perturbation spectra of apo- and heme-hemopexin near 290 nm, suggesting that slight or compensating changes in the exposure to solvent of tryptophan chromophores occur. In the Soret spectral region, the exposure of heme in the heme-hemopexin complex to ethylene glycol was 0.7, relative to the fully exposed heme peptide of cytochrome c. The fluorescence quantum yields of rabbit apo- and heme-hemopexin were estimated to be 0.06 and 0.03, respectively, compared to a yield of 0.13 for L-tryptophan. Iodide quenched 50% of the fluorescence of the deuteroheme-hemopexin complex. Cesium was not an effective quencher. Modification of approximately, 4 tryptophan residues with N-bromosuccinimide also decreased the relative fluorescence of apo-hemopexin by 50% and concomitantly reduced the heme-binding ability of the protein by 70%. The existence of sterically unhindered tryptophan residues in either apo- heme-hemopexin is unlikely since no charge transfer compelxes between these proteins and N-methylnicotinamide were detected.

Animals↗
PubMed1976

Transfer of heme from heme-albumin to hemopexin.

Exchange of heme in vitro between two heme-binding serum proteins, albumin and hemopexin, was examined spectrophotometrically. Hemopexin, albumin and heme in molar ratios of 1 : 70 : 1 were incubated at 22 degrees C, pH 7.3. The heme was added as free heme, heme-hemopexin or methemalbumin. Due to the high affinity of hemopexin for heme, Kd near 10(-13) M, only negligible amounts of heme were transferred from hemopexin to albumin in 48 h. However, more than 80% of heme was transferred from methemalbumin to hemopexin within 24 h. Heme added to a 1 : 70 mixture of the apo-proteins is initially bound by albumin; but more than 90% is bound by hemopexin in 24 h. Addition of dithionite causes nearly all of the heme present, whether added as free heme or methemalbumin, to associate with hemopexin in 15 min. Albumin thus appears to have a much lower affinity for ferro- than for ferri-heme. Results obtained from similar experiments with human serum and human serum made hemopexin-free by immunoadsorption fully corroborate those obtained with mixtures of purified albumin and hemopexin. These observations suggest that the rate-limiting step in the heme transport function of hemopexin is the formation of the heme-hemopexin complex, rather than the uptake of the complex by the liver.

Apoproteins↗
PubMed1978

Interaction of rabbit hemopexin with bilirubin.

The interaction of hemopexin with bilirubin was characterized by spectrophotometric, fluorimetric and circular dichroic techniques. Hemopexin rapidly forms an equimolar complex with libirubin that has an apparent dissociation constant Kd, of 7.5.10(-7) M. The association alters the absorption band of bilirubin near 150 nm, quenches the fluorescence of tryptophan residues of hemopexin, enhances the fluorescence of bilirubin, and induces strong ellipticity extrema in bilirubin of --60 . 10(3) deg . cm2 . dmol-1 at 465 nm and +70 . 10(3) deg . cm2 . dmol-1 at 415 nm. However, the conformation-sensitive ellipticity aband at 231 nm of hemopexin is not altered. In displacement experiments using circular dichroism, heme readily replaced bound bilirubin, indicating that bilirubin and heme are bound at the same site on hemopexin. Even at molar ratios of hemopexin to albumin of 3 to 1, human serum albumin removes bilirubin from hemopexin. Hemopexin is thus unlikely to have a role in the transport of bilirubin in serum.

Animals↗
PubMed1976

The binding and transport of heme by hemopexin.

Hemopexin binds proto-, meso-, or deutero-ferriheme with high affinity, forming an equimolar, low-spin complex. The ferroheme-hemopexin complex, which coordinates with CO and readily autoxidizes, is also low-spin. Formation of the ferriheme-hemopexin complex requires essential histidine and tryptophan residues and induces changes in the protein's tertiary structure. These changes may be important for the uptake of the heme-hemopexin complex by hepatocytes. Hemopexin also binds other porphyrins including protoporphyrin IX, and uro- and coproporphyrins I and III in a 1:1 molar ratio, but they are readily displaced by heme and do not produce discernable changes in the protein's conformation. In preliminary experiments, a selective interaction in vitro between heme-hemopexin and isolated rat hepatocytes has been demonstrated. This information is used as the basis for proposed models of the heme-binding site of hemopexin and of the interaction of heme-hemopexin with the parenchymal cells of the liver.

Animals↗
PubMed1978

Elevations of hemopexin levels in neuromuscular disease.

Hemopexin, a serum glycoprotein that binds free heme and transports it to hepatic parenchymal cells, has been measured by radial immunodiffusion. We have confirmed elevation of serum hemopexin concentration in Duchenne's muscular dystrophy patients and carries, and demonstrated elevations in dermatomyositis/polymyositis and myasthenia gravis, but not in amyotrophic lateral sclerosis. In monkeys, elevations of hemopexin levels were specifically induced by hematin injections, muscle-crush, or myoglobin injections. Myoglobin leakage is the likely explanation of hemopexin level elevation in Duchenne's dystrophy patients and carriers and in dermatomyositis/polymyositis. In myasthenia gravis there might be a slight myoglobin leakage not heretofore suspected; or, the elevation of hemopexin levels might be a new reflection of a dysimmune state in myasthenia gravis, and perhaps as such is a further incrementing factor in dermatomyositis/polymyositis. Hemopexin, presumably as a longer-phase reactant, is sometimes an index of neuromuscular disease when other data are negative or equivocal.

Animals↗
PubMed1975

Hemopexin synthesis in vitro by human fetal tissues.

Serum concentrations of hemopexin, transferrin, and albumin were measured for 12 fetuses between 14 and 36 weeks of gestational age. Hemopexin levels ranged from 7 to 64 mug/ml, transferrin levels ranged from 280 to 928 mug/ml, and albumin levels ranged from 13 to 59 mg/ml. In general, the serum concentrations of these three proteins increased with advancing gestation. Placenta, thymus, and colon did not incorporate 14C-labeled amino acids into hemopexin, transferrin, or albumin. By contrast radioimmune precipitates for five culture supernatants of liver indicated significant synthesis of albumin and hemopexin. [14C]Albumin accounted for 22-73% and [14C]hemopexin 1.1-4.2% of the total 14C-labeled proteins. In each instance, the [14C]transferrin was below 1% of the total 14C-labeled proteins.

Amino Acids↗
PubMed1975

Cellular and subcellular localization of heme and hemopexin in the rabbit.

The cellular distribution of intravenously administered 3H-heme, 125I-hemopexin and 125I-albumin was studied in rabbits. Radioautography of the tissue slides of several organs was examined by light and electron microscopy. All experiments were terminated 60 min after injection of the isotope-labeled materials. 3H-heme and native monomeric 125I-hemopexin (heme saturated) were found to be associated with the endoplasmic reticulum and microbodies of the hepatocytes. Aggregated hemopexin was also taken up by macrophages of lung alveoli, splenic pulp, interstitial cells of the kidney and Kupffer cells. 125I-albumin (heme saturated) could not be located in liver, spleen, bone marrow, lung, or kidney tissues.

Animals↗
PubMed1976

Genetic control of serum hemopexin.

Serum hemopexin was studied in a sample of twin pairs. Among monozygotic twin pairs a high concordance was found for serum hemopexin. This zygosity group analysis of variance also showed a significantly lower variance within than between pairs. The results indicate that the concentration of serum hemopexin is strongly influenced by genetic factors.

Analysis of Variance↗
PubMed1975

Catabolism of photo-oxidized and desialylated hemopexin in the rabbit.

Following injection of rabbit 125I-asialohemopexin, more than 90% of the protein-bound 125I was removed from the circulation of rabbits within 12 min. The amount of asialoprotein in the catabolic compartment reached a peak concentration (75 to 85%) 12 min after injection and was completely eliminated from this compartment within 2 hours. The degradation products were excreted into the urine, with 50 to 70% of the 125I eliminated during the first 24 hours and 90 to 95% excreted by 48 hours. Analysis of these data indicated an apparent first order rate constant for uptake of asialohemopexin of 0.32 min-1, for catabolism of 0.020 min-1 and for excretion of 0.054 to 0.093 hour-1. The plasma distribution curves of 125I-hemopexin, after the first 24 hours, showed essentially no difference. Both proteins were catabolized with an average T1/2 of 25 to 26 hours and a similar fractional catabolic rate. Simultaneous injection of heme and 125I-hemopexin resulted in rapid removal and catabolism of the protein. In contrast, injection of heme had little if any effect on the plasma radioactivity curve of photoinactivated 125I-hemopexin.

Animals↗
PubMed1979

Demonstration of the simultaneous presence of transferrin, hemopexin and albumin in the same adult rat hepatocyte.

The location of three plasma proteins (transferrin, hemopexin, and albumin) in hepatocytes was investigated in adult rats. The synthesis of transferrin anf hemopexin has been established by ultrastructural studies showing a labeling of the rough endoplasmic reticulum (RER). By using an indirect immunoenzymatic method with monospecific antibody solutions, the three proteins were detected in the same hepatocyte. The simultaneous presence of different plasma proteins in hepatocytes seems to point to the fact that the synthesis in these cells could be a non-specialized type.

Animals↗
PubMed1978

Immunological cross-reactions between heterologous hemopexins.

1. The degree of immunological identity of the hemopexin of 64 mammals and non-mammals is determined by double diffusion in agar and two radioimmunoassays, employing antisera produced with the human or the rabbit protein. 2. Antigenic determinants are shared by the Eutherian mammals but not by the non-Eutherian mammals and lower animals. 3. The hemopexins of man and apes appear to be identical, whereas those of Old World monkeys lack one antigenic determinant, and New World monkeys lack at least two antigenic determinants.

Animals↗
PubMed1976

Kinetics of the conformational changes of hemopexin in acid media.

Under the action of acid media the hemopexin molecule unfolds with resulting heme expulsion from the binding site, followed by heme dimerization and reassociation of dimeric heme with the unfolded protein molecule. The rate of the reaction is pH dependent and the whole process is fully reversible for a certain time interval. Prolonged treatment of hemopexin at acidic conditions, however, leads to the irreversible denaturation of this protein.

Heme↗
PubMed1978

The hemopexin locus: its assignment to linkage group I in the laboratory rabbit (Oryctolagus cuniculus) and evidence for a fourth allele.

The hemopexin locus phenotypes were determined for 450 animals with polyacrylamide gel electrophoresis, and the presence of a fourth allele at this locus was revealed. Of the 19 mating types segregating at this locus, 17 demonstrated segregation ratios consistent with the hypothesis of a four allele, codominant, autosomal system. Studies of three of our largest inbreeding lines indicated that fixation at this locus has occurred in two of them. Linkage studies showed that the Hx locus is located between the color locus, c, and the Hq blood group locus; therefore it is assigned to Linkage Group I of the rabbit.

Alleles↗
PubMed1975

Relationship of the biosynthesis of alpha-fetoprotein, albumin, hemopexin, and haptoglobin to the growth state of fetal rat hepatocyte cultures.

AFP and albumin are produced by arginine-synthesizing fetal rat hepatocytes in vitro. AFP and hemopexin production are coupled to hepatocellular proliferation, whereas albumin and haptoglobin production are not. During the cell cycle, AFP is synthesized prior to S and released prior to M. AFP may play a role in regulation of hepatocellular growth through estradiol binding and modulation of the intracellular concentration of lipoprotein (VLDL).

Albumins↗
PubMed1975

Haptoglobin, hemopexin, hemoglobin and hematocrit in newborns with erythrocyte glucose-6-phosphate dehydrogenase deficiency.

Hemolysis was studied in 40 G-6-PD-deficient newborn infants, half of whom had bilirubin blood levels within the normal range whereas the others, who were hyperbilirubinemic, underwent exchange transfusion. Hemoglobin, hematocrit, hemopexin and haptoglobin showed no or little differences between either of the two groups and the controls. The findings confirm the authors' assumption expressed elsewhere that this form of hyperbilirubinemia is not hemolytic in nature.

Bilirubin↗