Hemes synthesis lead interference with

Hematological Effects. Lead has long been known to have profound effects on heme synthesis. The impairment of heme synthesis has a far-ranging impact not limited to the hematopoietic system. EPA (1986a) summarized the known and potential consequences of the reduction of heme synthesis as shown in Figure 2-11. The mechanisms by which lead interferes with heme synthesis are discussed in Section 2.4.2. 

Lead interferes with the synthesis of heme, and its inhibitory effects on the enzymes of this pathway can be readily detected in humans. 

Lead interferes with vitamin D metabolism, since it inhibits hydroxylation of 25-hydroxy-vitamin D to produce the active form of vitamin D. The effect has been reported in children, with blood levels as low as 10-15 pg/lOO cm3 (WHO, 1986). Measurements of the inhibitory effects of lead on heme synthesis are widely used in screening tests to determine whether medical treatment for lead toxicity is needed for children in high-risk populations who have not yet developed overt symptoms of lead poisoning. 

A marked interference with heme synthesis results in a reduction of the hemoglobin concentration in blood. Decreased hemoglobin production, coupled with an increase in erythrocyte destruction, results in a hypochromic, normocytic anemia with associated reticulocytosis. Decreased hemoglobin and anemia have been observed in lead workers and in children with prolonged exposure at higher PbB levels than those noted as threshold levels for inhibition or stimulation of enzyme activities involved in heme synthesis (EPA 1986a). 

It is possible that lead s interference with heme synthesis may underlie the effects on vitamin D metabolism. Evidence that lead affects heme synthesis in the kidney was presented in the section on hematological effects. In addition, apparent thresholds for the effects of lead on renal vitamin D metabolism and for erythrocyte protoporphyrin accumulation are similar. 

Acute-Duration Exposure. There are few data available for acute exposures in humans. This may be a function of the time required for the expression of effects (decreased heme synthesis, neurobehavioral changes, increased blood pressure, and interference with vitamin D metabolism) and the usual modes of exposure in humans, which are repeated ingestion of lead-containing dirt or lead-based paint chips in... 

Lead causes damage to a variety of organs and also causes significant biochemical effects. Thus, the kidneys, testes, bones, gastrointestinal tract, and the nervous system are all damaged by lead. The major biochemical effect is interference with heme synthesis giving rise to anemia. 

Lead is a toxic metal to which there is wide exposure. Exposure is via inhalation (main source, leaded petrol) and ingestion (water, old paint). Multi-organ toxicity occurs with the kidneys, central and peripheral nervous system, testes, red cells, bones, and gastrointestinal tract all damaged. After initial distribution into red blood cells, it is eventually deposited in bone. The main biochemical effect is interference with heme synthesis at several points. Kidney toxicity may be due to lead-protein complexes and inhibition of mitochondrial function. Damage to nerves leads to peripheral neuropathy. 

Aluminium overload in uremic patients can lead to a microcytic hypochromic anemia (45). The mechanism is unknown, but it appears to involve inhibition of heme synthesis, either by inhibition of enzyme activity or by interference with the incorporation or utilization of iron. Exposure for 3 months is sufficient to reduce hematological values and cause significant increases in serum and urinary aluminium (46). The anemia can be reversed by lowering the aluminium intake or by chelation therapy with deferoxamine. 

An example of the latter is nickel, which can inhibit the synthesis of an enzyme, (5-aminolevulinic acid synthetase (ALAS) (Maines and Kappas, 1977). ALAS catalyzes synthesis of heme, an important component of hemoglobin and cytochrome. Thus, such metals as nickel or platinum, may affect the synthesis of heme. Also actions of metals may differ widely, as well as, the degree of susceptibility of enzymes to metals. For example, lead can inhibit several enzymes and therefore interfere with the synthesis of heme to a greater extent than nickel or platinum. 

Heavy metals stimulate or inhibit a wide variety of enzyme systems (16, 71, 72), sometimes for protracted periods (71, 73). These effects may be so sensitive as to precede overt toxicity as in the case of lead-induced inhibition of 8 ALA dehydrase activity with consequential interference of heme and porphyrin synthesis (15, 16). Urinary excretion of 8 ALA is also a sensitive indicator of lead absorption (74). Another erythrocytic enzyme, glucose-6-phosphatase, when present in abnormally low amounts, may increase susceptibility to lead intoxication (75), and for this reason, screens to detect such affected persons in lead-related injuries have been suggested (76). Biochemical bases for trace element toxicity have been described for the heavy metals (16), selenium (77), fluoride (78), and cobalt (79). Heavy metal metabolic injury, in addition to producing primary toxicity, can adversely alter drug detoxification mechanisms (80, 81), with possible secondary consequences for that portion of the population on medication. 

Fig. 2. Steps in the enzymatic synthesis of heme with which interferes. This interference can lead to the production of defective red blood cells...

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