Heme synthesis

Lowest observed effect level (PbB) (Mg/dl) Heme synthesis and hematological effects Neurological effects Renal system effects Gastrointestinal effects ... 

The final step in heme synthesis involves the incorporation of ferrous iron into protoporphyrin in a reaction catalyzed by ferrochelatase (heme synthase), another mitochondrial enzyme (Figure 32-4). 

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. 

The most common method used to monitor inorganic Pb is the determination of Pb in whole blood by GF-AAS. Exposure to organic lead (i.e. tetraethyl lead) can be monitored by the determination of Pb in mine by GF-AAS (Christensen and Kristiansen 1994). Early effects of exposure to Pb on the heme synthesis can be monitored by determination of the inhibition of the enayme 8-aminolevulinic acid dehydratase in whole blood or 8-aminolevulinic acid in urine by spectrophotometry. 

Alterations in blood heme metabolism have been proposed as a possible indicator of the biological effects of hydrogen sulfide (Jappinen and Tenhunen 1990), but this does not relate to the mechanism of toxicity in humans. The activities of the enzymes of heme synthesis, i.e., delta-aminolevulinic acid synthase (ALA-S) and heme synthase (Haem-S), were examined in 21 cases of acute hydrogen sulfide toxicity in Finnish pulp mill and oil refinery workers. Subjects were exposed to hydrogen sulfide for periods ranging from approximately 1 minute to up to 3.5 hours. Hydrogen sulfide concentrations were considered to be in the range of 20-200 ppm. Several subjects lost consciousness for up to 3 minutes. 

Effect. Potential biomarkers of the subclinical effects of hydrogen sulfide are decreases in the activities of the heme synthesis enzymes, ALA-S and Haem-S (Jappinen and Tenhunen 1990). These effects have nothing to do with the mechanism of toxicity, however. Neurological indices are also used as biomarkers of effect for hydrogen sulfide (Gaitonde et al. 1987 Kilbum 1993 Stine et al. 1976 Tvedt et al. 1991b). 

The data from the only available animal study (Prigge and Greve 1977) indicate that inhaled lead is not teratogenic. However, it impaired heme synthesis in both rat dams and fetuses. In this study, dams were exposed to 1, 3, or 10 mg lead/m3 (chemical species not provided) throughout gestation (days 1-21). Maternal and fetal ALAD were inhibited at all exposure levels in a dose-related manner, and fetal (but not maternal) hematocrit and body weight were decreased at the 10-mg/m3 lead level. These results suggest that the fetuses were more sensitive to lead-induced toxicity than were the dams. 

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. 

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). 

The impairment of heme synthesis by lead has a far-ranging impact not limited to the hematopoietic system. EPA (1986a) provided an overview of the known and potential consequences of the reduction of heme synthesis as shown in Figure 2-11. Well documented effects are indicated by solid arrows, and effects considered to be plausible further consequences of the impairment of heme synthesis are indicated by dashed arrows. Additional discussion is provided in the following sections on renal and neurological effects. More detailed information on the exposure levels or blood lead levels at which these impacts may be experienced was provided in Section 2.2 and the relevance to human health is discussed in Section 2.5. 

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. 

Health effects that have been associated with lead exposures during infancy or childhood include, anemia (Schwartz et al. 1990) (and related disorders of heme synthesis), neurological impairment (e.g., encephalopathy), renal alterations, and colic (Chisolm 1962, 1965 Chisolm and Harrison 1956), and impaired metabolism of vitamin D (Mahaffey et al. 1982 Rosen and Chesney 1983). Death from encephalopathy may occur with PbB levels 125 pg/dL. In addition to the above effects, the following health effects have been associated with lead exposures either in utero, during infancy or during... 

Certain subgroups of the population may be more susceptible to the toxic effects of lead exposure. These include crawling and house-bound children (<6 years old), pregnant women (and the fetus), the elderly, smokers, alcoholics, and people with genetic diseases affecting heme synthesis, nutritional deficiencies, and neurological or kidney dysfunction. This is not an exhaustive list and reflects only current data available, further research may identify additional susceptible subgroups. 

Susceptibility to lead toxicity is influenced by dietary levels of calcium, iron, phosphorus, vitamins A and D, dietary protein, and alcohol (Calabrese 1978). Low dietary ingestion of calcium or iron increased the predisposition to lead toxicity in animals (Barton et al. 1978a Carpenter 1982 Hashmi et al. 1989a Six and Goyer 1972 Waxman and Rabinowitz 1966). Iron deficiency combined with lead exposure acts synergistically to impair heme synthesis and cell metabolism (Waxman and Rabinowitz 1966). 

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... 

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