Liver heme synthesis

Many drugs when administered to humans can result in a marked increase in ALASl. Most of these drugs are metabolized by a system in the liver that utilizes a specific hemoprotein, cytochrome P450 (see Chapter 53). During their metabolism, the utilization of heme by cytochrome P450 is greatly increased, which in turn diminishes the intracellular heme concentration. This latter event effects a derepression of ALASl with a corresponding increased rate of heme synthesis to meet the needs of the cells. 

Studies in animals indicate that the effects of lead on heme synthesis occur in many tissues and that the time courses of these effects depends on the tissue, exposure duration, and the chemical and animal species administered. Oral exposure of rats to lead acetate increased liver ALAS activity in a single dose study (Chmielnicka et al. 1994), decreased liver ALAS activity in a chronic study (Silbergeld et al. 

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. 

Increased ALA synthase activity One common feature of the j porphyrias is a decreased synthesis of heme. In the liver, heme normally functions as a repressor of ALA synthase. Therefore, Ihe absence of this end product results in an increase in the synthesis of ALA synthase (derepression). This causes an increased syn thesis of intermediates that occur prior to the genetic block. The accumulation of these toxic intermediates is the major pathophysi ology of the porphyrias. 

Heme synthesis is controlled primarily by 8-aminolevulinate synthase (ALA synthase). There are two mechanisms of control, and each involves a process that affects the concentration of the enzyme. First, the half-life of ALA synthase, as shown by experiments in rat liver, is very short (60-70 min). Like many mitochondrial proteins, ALA synthase is encoded by nuclear genes, synthesized on cytoplasmic ribosomes, and the enzyme is translocated into the mitochondria. The second and main regulating factor is the inhibition of ALA synthase by hemin. Hemin differs from heme in that the Fe atom is in the Fe3+ oxidation state. Heme spontaneously oxidizes to hemin when there is no globin to form hemoglobin. Hemin serves a second function in the regulation of hemoglobin synthesis in reticulocytes. It controls the synthesis of globin. 

Ascorbate is edso active in the reduction of Fe + in the pltisma treuisport protein, transferrin, to Fe + for storage in ferritin in the liver or for heme synthesis. It is not clear to what extent this represents specific actions of ascorbate, because other reducing reagents, including glutathione, tdso enhtmce heme synthesis, emd the NADH-dependent flavoprotein ferriducttise is the major factor controlling the transfer of iron between tremsferrin and ferritin. 

The co-administration of M. oleifera seed powder with arsenic protects animals from arsenic induced oxidative stress and reduce body arsenic burden (49). Exposure of rats to arsenie (2.5 mg/kg, intraperitoneally for 6 weeks) increases the levels of tissue reaetive oxygen species (ROS), metallothionein (MT) and thiobarbitnrie aeid reaetive substance (TEARS) and is accompanied by a decrease in the aetivities in the antioxidant enzymes such as superoxide dismutase (SOD), eatalase and glutathione peroxidase (GPx). Also, Arsenic exposed mice exhibits hver injury as reflected by reduced acid phosphatase (AGP), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) activities and altered heme synthesis pathway as shown by inhibited blood 8-aminolevulinic acid dehydratase (5-ALAD) activity. Co-administration of M. oleifera seed powder (250 and 500 mg/kg, orally) with arsenie significantly increases the activities of SOD, catalase, GPx with elevation in redueed GSH level in tissues (liver, kidney and brain). These ehanges are accompanied by approximately 57%, 64% and 17% decrease in blood ROS, liver metallothionein (MT) and lipid peroxidation respectively in animal eo-administered with M. oleifera and arsenic. There is a reduced uptake of arsenie in soft tissues (55% in blood, 65% in liver, 54% in kidneys and 34% in brain) following eo-administration of M. oleifera seed powder (particularly at the dose of 500 mg/kg). This points to the fact that administration of M. oleifera seed powder could be beneficial during chelation therapy with a thiol chelator (26). 

In several studies hematocrit, hemoglobin and serum iron levels were not affected by dietary calcium and phosphorus levels, but other parameters such as liver or bone iron levels were affected (44,45.47.59). This is not surprising as it is generally recognized that iron stores must be depleted before heme synthesis is impaired (67), Similarly the methods used to assess zinc status in the various studies differed in sensitivity. Less is known about optimal ways to assess zinc status, but generally bone zinc levels are considered to be a more sensitive indicator than serum or liver zinc levels of nutritional status of animals in regard to zinc (68). 

The primary regulatory step of heme synthesis in the liver is apparently that catalyzed by ALA synthase. The regulatory effects are multiple. The normal end product, heme, when in excess of need for production of heme proteins, is oxidized to hematin, which contains a hydroxyl group attached to the Fe + atom. Replacement of the hydroxyl group by a chloride ion produces hemin. Hemin and heme inhibit ALA synthase allosterically. Hemin also inhibits the transport of cytosolic ALA synthase precursor protein into mitochondria. 

In most of these disorders, increased hepatic ALA synthase activity is due to decreased heme synthesis. There are also increased amounts of ALA and porphobilinogen in liver, plasma, and urine and specific... 

Fig. 20.17. Efflux of intermediates from the TCA cycle. In the liver, TCA cycle intermediates are continuously withdrawn into the pathways of fatty acid synthesis, amino acid synthesis, gluconeogenesis, and heme synthesis. In brain, a-ketoglutarate is converted to glutamate and GABA, both neurotransmitters.

D.L. Stout, F.F. Becker (1990). Heme synthesis in normal mouse liver and mouse liver tumors. Cancer Res., 50, 2337-2340. 

In chick embryo liver cells, thujone has demonstrated porphyrogenic activity on this basis, it has been suggested that it could be hazardous to patients with acquired or genetic defects of heme synthesis in the liver (Bonkovsky et al. 1992). 

Porphyrias clinical conditions resulting from genetic defects in heme biosynthesis. For the pathway of heme biosynthesis, see Porphyrins. Inborn errors have been described for 7 of the 8 enzymes in this pathway. Although no major genetic defect has been described for the first enzyme of the pathway, S-aminolevulinate synthase (EC 2.3.1.37), low activity has been reported in a case of congenital sideroblastic anemia [G. R. Buchanan et al. Blood 55 (1980) 109-115]. Heme is an essential constituent of many important enzymes and hemoproteins. Absence of heme synthesis is therefore incompatible with life, and homozygotes of inherited autosomal dominant disorders of heme synthesis are not viable, unless there is residual activity of the enzyme concerned. P. are classified as erythropoietic or hepatic, depending on whether the defect is located mainly in the erythroid cells or the liver. 

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]. 

After it had been shown in chick embryo liver culture treated with inhibitors that RNA and protein synthesis were required for induction of ALA-synthetase [24,25], these results were confirmed in whole-animal studies [77-79]. Narisawa and Kikuchi [79] were able to detect an increase of ALA-synthetase in the liver 1 to 2 hours after a single subcutaneous dose of 400 mg of ALA per kilogram. It was also shown that not only porphyrins but heme synthesis was increased in chemical porphyria. DeMatteis and Rimington [80], using 2- " C-glycine or Fe, found an increased heme labeling in the presence of the inducers sedormid, AIA, and griseofulvin. It was not determined whether total heme was increased or whether heme turnover had increased. 

In this section, the activities of inducing chemicals are discussed in relation to their destruction by the liver microsomal oxygenase system the rate of heme synthesis and breakdown is considered in relation to the inhibitory properties of heme on the synthesis of ALA-synthetase and the contrasting effects of glucose and starvation are summarized in relation to their effects on induction. 

D. Heme Synthesis in the Liver, Heme Oxygenase, and Early Labeled Bilirubin... 

Physiologically, microsomal oxidation via the cytochromes appears to serve for the lipophilic oxidation of steroids, fatty acids, heme, and drugs. The microsomal cytochromes and smooth endoplasmic reticulum may be controlled in part by steroids. For example, the relatively high production of heme by normal liver suggests that there may be natural 5/i-H steroids that normally serve to maintain a certain rate of heme synthesis by inducing the synthesis of ALA-synthetase. An... 

Under normal conditions, the main pathway for porphobilinogen is its conversion to protoporphyrin IX and heme. Heme is used for heme protein synthesis in the liver (cytochromes, and such enzymes as catalase). An alternative pathway for porphobilinogen is its transformation to uro- and coproporphyrin I, which are not further used by cellular metabolism. A block in porphobilinogen use for heme synthesis is likely to divert the porphobilinogen into the alternative pathway, and then uroporphyrin I accumulates. This does not occur in acute intermittent porphyria. 

Copper Cu Anemia ataxia defective melamine production and keratinization Liver necrosis, e.g. in Wilson s disease hypertension Copper is a component of oxidative enzymes involved in heme synthesis... 

Tephly TR, Hasegawa D, Baron J (1971) Effects of drugs on heme synthesis in the liver. Metabolism 20 200-210... 

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