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Biomedical subjects

R Schmid

Publications and source records attributed to R Schmid.

At least 397 records · Page 22Linked to original sources
PubMed1971

The enzymatic degradation of hemoglobin to bile pigments by macrophages.

Recent studies have identified and characterized the enzymatic mechanism by which hemoglobin-heme is converted to bilirubin. Under physiologic conditions the enzyme system, microsomal heme-oxygenase, is most active in the spleen followed by the liver and bone marrow, all of which are tissues that normally are involved in the sequestration and metabolism of red cells. Indirect evidence suggested that the reticuloendothelial system is important in this process. To test this hypothesis, conversion of heme to bilirubin was studied in macrophages obtained by chemical or immunological means from the peritoneal cavity or from the lungs of rodents. Homogenates of pure populations of these cells were devoid of heme-oxygenase activity, unless before harvesting the macrophages had been exposed to methemalbumin, microcrystalline hemin, or hemoglobin in vivo. In macrophages exposed to heme pigments, the specific activity of heme-oxygenase was far in excess of that in the spleen or liver. Enzyme activity was also present in the granulomatous tissue surrounding subcutaneous hematomas. The heme-oxygenase system in macrophages resembles that in the spleen and liver in that it is localized in the microsomal fraction, has an absolute requirement for molecular oxygen and NADPH, is inhibited by carbon monoxide, and has a similar K(m). These findings indicate that cells of the reticuloendothelial system, presumably including the Kupffer cells of the liver and the macrophages of the spleen, possess the enzymatic machinery for converting hemoglobin-heme to bilirubin. The reaction is a mixed function oxidation, probably involving cytochrome P450 as the terminal oxidase. Enzyme activity in macrophages is capable of regulatory adaptation in response to substrate loads. In the standard assay system for the enzyme, disappearance of heme always was in excess of the amount of bilirubin formed, suggesting the simultaneous presence of alternate routes of heme degradation not involving bilirubin as an end product or intermediate.

Albumins↗
PubMed1971

Erythropoietic protoporphyria: evidence for multiple sites of excess protoporphyrin formation.

A patient with erythropoietic protoporphyria was studied to determine the sites of excess protoporphyrin formation. The patient's protoporphyrin was pulse labeled by the simultaneous administration of the precursors 2-glycine-(14)C and 3,5-delta-aminolevulinic acid-(3)H; delta-aminolevulinic acid preferentially labels the hepatic pool. Blood and feces were studied at intervals for the next 14 days. Protoporphyrin was extracted from erythrocytes, plasma, and feces, identified by thin-layer chromatography, and quantitated spectrophotometrically, and its specific activity was determined by liquid scintillation spectrometry. Analysis of the kinetic and isotopic data indicated at least two sources of protoporphyrin, one localized in the erythroid cells, a second in the liver. The liver was responsible for the majority of the excess protoporphyrin. This report thus provides evidence of a genetic porphyria exhibiting an abnormality of porphyrin biosynthesis in at least two tissues. We propose that the disease, erythropoietic protoporphyria, be renamed erythrohepatic protoporphyria.

Adult↗
PubMed1971

Inducible heme oxygenase in the kidney: a model for the homeostatic control of hemoglobin catabolism.

We have recently identified and characterized NADPH-dependent microsomal heme oxygenase as the major enzymatic mechanism for the conversion of hemoglobin-heme to bilirubin-IXalpha in vivo. Enzyme activity is highest in tissues normally involved in red cell breakdown, that is, spleen, liver, and bone marrow, but it usually is negligible in the kidney. However, renal heme oxygenase activity may be transiently increased 30- to 100-fold following hemoglobinemia that exceeded the plasma haptoglobin-binding capacity and consequently resulted in hemoglobinuria. Maximal stimulation of enzyme activity in rats is reached 6-16 hr following a single intravenous injection of 30 mg of hemoglobin per 100 g body weight; activity returns to basal levels after about 48 hr. At peak level, total enzyme activity in the kidneys exceeds that of the spleen or liver. Cyclohexamide, puromycin, or actinomycin D, given just before, or within a few hours after, a single intravenous injection of hemoglobin minimizes or prevents the rise in renal enzyme activity; this suggests that the increase in enzyme activity is dependent on continued synthesis of ribonucleic acid and protein. The apparent biological half-life of renal heme oxygenase is about 6 hr. These observations indicate that functional adaptation of renal heme oxygenase activity reflects enzyme induction either directly or indirectly by the substrate, hemoglobin. Filtered rather than plasma hemoglobin appears to regulate renal heme oxygenase activity. Thus, stabilization of plasma hemoglobin in its tetrameric form with bis (N-maleimidomethyl) ether, which diminishes its glomerular filtration and retards it plasma clearance, results in reduced enzyme stimulation in the kidney, but enhances its activity in the liver. These findings suggest that the enzyme is localized in the tubular epithelial cells rather than in the glomeruli and is activated by luminal hemoglobin. Direct support for this concept was obtained by the demonstration of heme oxygenase activity in renal tubules isolated from rabbits that had been injected with hemoglobin.

Adaptation, Physiological↗
PubMed1970

Catabolism of heme in vivo: comparison of the simultaneous production of bilirubin and carbon monoxide.

The quantitative relationship between the catabolism of heme and the formation of bilirubin and carbon monoxide (CO) was studied in untreated rats and in animals treated with phenobarbital or the porphyrogenic drug, allylisopropylacetamide (AIA). A novel metabolic chamber permitting continuous collection of the bile and breath was utilized for quantitation of bilirubin-(14)C and (14)CO after the administration of hematin-(14)C or glycine-(14)C. After intravenous infusion of hematin-(14)C, control and phenobarbital-treated rats produced equimolar amounts of labeled bilirubin and CO; a minor fraction of the infused radioactivity appeared in the bile in other metabolites. The equimolar relationship in the formation of bilirubin and CO was also observed after pulse-labeling with glycine-2-(14)C; in phenobarbital-treated rats both metabolites were formed at an increased rate as compared to controls. By contrast, AIA treatment reduced the fractional conversion of hematin-(14)C to bilirubin and CO; a major fraction of the infused radioactivity appeared in the bile in metabolites other than bilirubin. In addition, in AIA-treated animals the molar CO/bilirubin recovery ratio was consistently greater than 1.0. Comparable results were obtained in AIA-treated rats after pulse-labeling with glycine-2-(14)C. These findings suggest that (a) in control and phenobarbital-treated rats infused hematin and heme formed in the liver are converted predominantly to bilirubin and CO, appearing in equimolar amounts; only a minor fraction of the hematin is degraded to other metabolites; (b) treatment with phenobarbital results in a proportional increase in the formation of both bilirubin and CO, reflecting increased heme synthesis and degradation in the liver; and (c) treatment with the porphyrogenic drug AIA shifts the CO/bilirubin ratio in favor of the gas, and enhances the formation of nonbilirubin metabolites.

Animals↗