Erythrocyte ALA Dehydratase

The inhibition of ALAD in erythrocytes serves as a highly sensitive indicator of environmental lead exposure in humans. As shown in Fig. 6, 

ALAD may not be well suited as a biomarker of lead exposure at blood lead levels greater than 50//g/dl. The decrease in ALAD activity is accompanied by a concomitant increase in the total amount of ALAD protein in erythrocyte precursors. At blood lead levels of 40-50//g/dl the amount of ALAD reaches a plateau corresponding to about two times the normal concentration, probably reflecting the maximum capacity of ALAD synthesis (Bernard and Lauwerys 1987). The practical consequence of this phenomenon is that assessment of ALAD activity alone does not accurately reflect the extent of enzyme inhibition at higher blood lead levels. 

Genetically linked deficiencies of erythrocyte ALAD in human subjects have been described by a number of investigators (Bird et al. 1979 Doss and Muller 1982 Benkmann et al. 1983 Astrin et al. 1987 Wetmur et al. 1991). In normal individuals, ALAD activity is sufficiently high, even under conditions of moderate lead toxicity, to sustain heme biosynthesis without the prospect of clinical effects related to heme deficiency. In contrast, when ALAD levels are significantly reduced due to an inherited deficiency of this enzyme, affected individuals could be at greater risk of lead toxicity related 

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Fig. 6. Relationship between erythrocyte ALA dehydratase activity and blood lead level. (Adapted from Sassa 1978)...

The concentration of lead in blood is an indication of recerd absorption of the metal. Clinical manifestations associated with increasing concentrations of lead in blood are shown in Figure 65-2. Children with concentrations of lead in blood >10 pg/dL are at risk ( developmental disabilities. Adults with concentrations <30 pg/dL exhibit no known functional injury or symptoms however, they will have a definite decrease in S-ALA dehydratase activity, a slight increase in urinary excretion of S-ALA, and an increase in erythrocyte protoporphyrin. Patients with a blood lead concentration of 30-75 pg/dL have all the preceding laboratory abnormalities and, usually, nonspecific, mild symptoms of lead poisoning. Clear symptoms of lead poisoning are associated... 

Four methods are known for porphobilinogen (PBG) production (i) isolation from human or animal urine (ii) chemical synthesis from 5-aminolevulinic acid (ALA) (iii) enzymatic synthesis using ALA dehydratase (the enzyme is isolated from erythrocytes, P. shermanii or Rhodopseudomonas sphaeroides) and (iv) microbiological production using heat-treated cells of P. shermanii, incubated in a medium containing ALA. 

ALA dehydratase, the second enzyme of the heme biosynthetic pathway, is inhibited in vitro by metals and other SH-directed agents. Inhibition of ALA dehydratase in liver and erythrocytes in vitro has been observed with silver, iron, manganese, copper, and zinc ions (Gibson et al. 1955) and in vivo with lead (Sassa 1978) and cobalt (Nakemura et al. 1975). The inhibition of ALA dehydratase in erythrocytes by lead in vivo is well established, and this effect is considered a highly sensitive measure of lead exposure in human subjects (considered further in Sect. D.I, below). 

Measurement of blood lead levels and other biological indices of lead exposure were carried out annually. These other biological indices are blood delta-aminolaevulinic acid concentrations, the activity of ALA dehydratase in blood, and erythrocyte protoporphyrin concentrations. In addition, deciduous tooth lead concentrations will be measured. 

Various minor hematological effects have been noted in animals. Rats exposed to 50-800 ppm of trichloroethylene continuously for 48 or 240 hours showed time- and dose-related depression of delta-aminolevulinate dehydratase activity in liver, bone marrow, and erythrocytes (Fujita et al. 1984 Koizumi et al. 1984). Related effects included increased delta-aminolevulinic acid (ALA) synthetase activity, reduced heme saturation of tryptophan pyrrolase and reduced cytochrome P-450 levels in the liver and increased urinary excretion of... 

ALA = 5-aminolevulinic acid ALAD = 6-aminolevulinic acid dehydratase ALAS = 5-aminolevulinic acid synthase EP = erythrocyte protoporphyrins FEP = free erythrocyte protoporphyrins FSH = follicle stimulating hormone IQ = intelligence quotient LH = luteinizing hormone NS = not specified (occup) = occupational Py-5 -N = pyrimidine-5-nucleotidase TSH = thyroid stimulating hormone ZPP = erythrocyte protoporphyrin... 

Schmitt, C.J., F.J. Dwyer, and S.E. Finger. 1984. Bioavailability of Pb and Zn from mine tailings as indicated by erythrocyte d-aminolevulinic acid dehydratase (ALA-D) activity in suckers (Pisces Catostomidae). Canad. Jour. Fish. Aquat. Sci. 41 1030-104). 

Hematological effects Decreased heme biosynthesis by inhibiting d-aminolevulinic acid dehydratase (ALAD) and ferrochelatase activity, an increase in blood and plasma d-aminolevulinic acid (ALA) and free erythrocyte protoporphyrins, hemolytic anemia and Frank anemia... 

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