Bone marrow, heme synthesis

Absorption, transport, and storage of iron. Intestinal epithelial cells actively absorb inorganic iron and heme iron (H). Ferrous iron that is absorbed or released from absorbed heme iron in the intestine (1) is actively transported into the blood or complexed with apoferritin (AF) and stored as ferritin (F). In the blood, iron is transported by transferrin (Tf) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hgb) (2) or to hepatocytes for storage as ferritin (3). The transferrin-iron complexes bind to transferrin receptors (TfR) in erythroid precursors and hepatocytes and are internalized. After release of the iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin (4). Hepatocytes use several mechanisms to... 

Heme, an iron-containing tetrapyrrole pigment, is a component of 02-binding proteins (see p. 106) and a coenzyme of various oxi-doreductases (see p. 32). Around 85% of heme biosynthesis occurs in the bone marrow, and a much smaller percentage is formed in the liver. Both mitochondria and cytoplasm are involved in heme synthesis. 

Heme synthesis takes place in all cells, but most of the body s heme is made in the liver and bone marrow. 

Lead poisoning produces a microcytic anemia that arises from the abiiity of iead to biock erythro-poiesis by inhibiting heme synthesis in the bone marrow at two steps. 

The answer is C. The patient s symptoms represent a composite of neurologic and gastrointestinal dysfunction, which are consistent with the anemia that is due to lead poisoning. Testing for lead would be appropriate for the patient, the other members of the household, and the house itself. Inorganic lead produces the microcytic anemia by inhibition of heme synthesis in erythropoietic cells of the bone marrow. All the other options represent enzymes of heme synthesis or degradation, but none of them are affected by lead. 

Tissues that synthesize heme, and the sources of porphyrin s carbon and nitrogen The major sites of heme biosynthesis are the liver (where the rate of synthesis is highly variable) and the erythrocyte-producing cells of the bone marrow (where the rate is generally constant). All the carbon and nitrogen atoms are provided by glycine and succinyl CoA. 

Acute lead toxicity produces appetite loss and vomiting. Chronic toxicity leads to renal malfunction, anemia, gout, and nervous system disorders, including brain damage in children. (Lead inhibits development in fetal and child brains.) The effects are more serious for a patient deficient in calcium, zinc, or iron (see Figure 2). Available Pb + affects the structure and function of the bone marrow, where it inhibits several enzymes involved in heme synthesis. It also affects mitochondrial functions in diverse ways. It has proven difficult, however, to specify critical interactions in lead toxicity. Pb + is not particularly carcinogenic but quite toxic. Acute toxicity is dealt with by infusion of Ca +-EDTA,... 

The complex tetrapyrrole ring structure of heme is built up in a stepwise fashion from the very simple precursors sue-cinyl-CoA and glycine (Figure 32-2). The pathway is present in all nucleated cells. From measurements of total bilirubin production, it has been estimated that daily synthesis of heme in humans is 5 to 8mmol/kg body weight. Of this, 70% to 80% occurs in the bone marrow and is used for hemoglobin synthesis. Approximately 15% is synthesized in the liver and is used to produce cytochrome P-450, mitochondrial cytochromes, and other hemoproteins. The pathway is compartmentalized, with some steps occurring in the mitochondrion and others in the cytoplasm. Little is known about the transport of intermediates across the mitochondrial membrane, and no transport defect has yet been reported in the porphyrias. 

Suboptimal erythropoiesis can be classified by changes in the size of RBCs noted on examination of the peripheral blood. Because the excretory and endocrine functions of the kidney usually mirror each other, renal dysfunction can lead to anemia by reduction in EPO production, resulting in a normochromic, normocytic pattern. Other causes of insufficient erythropoiesis include replacement of bone marrow by fibrosis, solid tumors, or leukemia, as well as defects in erythroid maturation. Relative deficiencies in the cofactors required for heme-RBC synthesis such as iron, folate, and vitamin B may also be important contributors. Structurally, RBC macrocytosis denotes defects in the maturation of the nucleus, whereas microcytosis is indicative of cytoplasmic defects (reduced hemoglobin synthesis). (A detailed description regarding the pathogenesis and treatment of anemic disorders is found in Chap. 99.)... 

Dose-related erythroid suppression probably reflects inhibition of mitochondrial protein synthesis in erythroid precursors, which impairs iron incorporation into heme. Bone marrow suppression occurs regularly with plasma concentrations >25 pg/mL and is observed with large doses of chloramphenicol, prolonged treatment, or both. Dose-related bone marrow suppression may progress to aplasia if treatment is continued, but most cases of aplasia develop without prior dose-related marrow suppression. 

Approximately 210 mg of heme are formed daily in the bone marrow of the adult to replace the hemoglobin lost through red cell breakdown. Since eight molecules of ALA are required to form one molecule of heme, about 358 mg of ALA are required for this amount of heme synthesis. In the inherited disease AIP, the liver may readily produce this much or more ALA yet normally the liver makes only about 15% of the ALA that is made by the bone marrow. It is obvious, therefore, that in the liver there is an important control mechanism for ALA synthesis revealed by this disease. Depending on the type of hepatic porphyria, the ALA which is produced may be excreted together with porphobilinogen in the urine, or it may excreted in the form of porphyrins in the urine and feces [2,4,6,11]. 

The requirement of pyridoxal phosphate for heme synthesis was first shown by a nutritional experiment. In 1950 Wintrobe [47] found that pigs deficient in vitamin Bg formed small, pale, red cells very low in free protoporphyrin, stored excessive iron, and had a h3q)erplastic bone marrow. Lascelles [8] showed that both vitamin Bg and pantothenic acid were required for porphyrin synthesis in Tetrahymena vorax. Similarly, studies by Schulman and Richert [48] showed that heme synthesis in deficient ducklings required vitamin Bg and CoA. 

In vitro studies of bone marrow proliferation (heme and hemoglobin synthesis) have established that those processes are not accelerated by increasing the oxygen tension. In fact, normoblastic mitosis is reduced when the oxygen tension is reduced in the entire medium. 

Toxic Properties. The toxic properties of metal ions such as Pb +, Hg +, Cd +, etc. are the result of the incorporation of some biological structure into the coordination sphere of the metal ion. The direct consequence of this is to alter the biological properties of these newly coordinated species, often by deactivation of any normal enzymatic activity. This can be clearly seen in the anemia characteristic of lead intoxication. Thus Pb2+ reacts with and reduces the activity of three of the enzymes involved in the synthesis of heme and reduces the ability of the stem cells in the bone marrow to form normal red blood cells (29). 

The etiology of microcytic hypochromic anemias as a class can be ascribed to decreased hemoglobin synthesis. Al has been shown to inhibit hemoglobin synthesis in Friend erythroleukemia cells (Abreo et al. 1990) and in bone marrow cells (Zamen et al. 1992), where it also accumulates. In vitro studies evaluating incorporation of Fe " into heme have identified heme, rather than globin, synthesis as the inhibited pathway in uremia (Moriyama et al. 1975). The most common cause of a fault in heme synthesis leading to microcytic anemia is iron deficiency or lack of availability. Although Al-related anemia is refractory to Fe, the anemia could be caused by an interaction between Al and Fe metabolism. 

Moriyama Y, Rege A, Fisher JW (1975) Studies on an inhibitor of erythropoesis ii. Inhibitory effects of serum from uremic rabbits on heme synthesis in rabbit bone marrow culture. Proc Soc Exp Biol Med 148 94-97 Moshtaghie AA, Bazrafshan MR (1992) Comparative binding study of aluminum and chromium to human transferrin effect of iron. Biol Trance Elem Res 32 39-45... 

The porphyrias result from inherited deficiencies in one of the seven enzymes of heme biosynthetic pathway (Fig. 31.1) [1]. Heme synthesis is most prominent in two organs, in bone marrow and liver. Therefore, porphyrias are classified as hepatic porphyrias or as erythropoietic porphyrias according to the tissue of excess porphyrin production. 

Immature red blood cells can use inorganic Fe++ for heme synthesis (164). However this is not a normal physiological process. Two mechanisms appear to be used for iron incorporation into immature red cells of the bone marrow. One is the adsorption of Fe-transferrin (a jS-globulin of the serum specific for iron transport) onto specific sites of the erythroblast or reticulocyte then the iron is transferred into the cell (as an iron complex or by pinoc3dosis of transferrin ) and is used directly for heme formation or... 

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