ALAD -aminolevulinic acid

ALAD = aminolevulinic acid dehydratase d = day(s) F = female Gd = gestational day Hemato = hematological hr = hour(s) LDH = lactatate dehydrogenase LOAEL = lowest-observable-adverse-effect level M = male NOAEL = no-observable-adverse-effect level Resp = respiratory wk = week(s). 

ALAD—aminolevulinic acid dchydrotase DDE—2,2-bis(p-phenol)-l,l,-,l,l-trichloro-2,2-bis (chlorophenyl) ethane Dicofol—2,2,2,-trichloro-1,1 OCs—organochlorines OPs—organophosphates PAHs—polycyclic aro-EQ—dioxin equivalents. 

ALAD (8-aminolevulinic acid dehydratase) Aldehydes (screening)... 

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... 

In summary, lead inhibits the activity of certain enzymes involved in heme biosynthesis, namely, 5-aminolevulinic acid dehydratase (ALAD), and ferrochelatase. As a consequence of these changes, heme biosynthesis is decreased and the activity of the rate limiting enzyme of the pathway,... 

ALAD = delta-aminolevulinic acid dehydratase DMSA= dimercaptosuccinic acid NMDA= N-methyl- D-aspartate PCBs = polychlorinated biphenyls XRF = X-ray fluorescence... 

Dieter, M.P. 1979. Blood delta-aminolevulinic acid dehydratase (ALAD) to monitor lead contamination in canvasback ducks (Aythya valisineria). Pages 177-191 in National Academy of Sciences. Animals as Monitors of Environmental Pollutants. Washington, D.C. 

EXDVXXGXPPAA Delta-aminolevulinic acid dehydratase, chloroplast precursor (porphobilinogen synthase) (ALADH) (ALAD)/ 60-94 Selaginella martensii 100% 0.05... 

Enzyme Inhibition/Activation. A major site of toxic action for metals is interaction with enzymes, resulting in either enzyme inhibition or activation. Two mechanisms are of particular importance inhibition may occur as a result of interaction between the metal and sulfhydryl (SH) groups on the enzyme, or the metal may displace an essential metal cofactor of the enzyme. For example, lead may displace zinc in the zinc-dependent enzyme 5-aminolevulinic acid dehydratase (ALAD), thereby inhibiting the synthesis of heme, an important component of hemoglobin and heme-containing enzymes, such as cytochromes. 

Displacing the Essential Metal Ion in Biomolecules. It is estimated that approximately one third of all enzymes require metal as a cofactor or as a structural component. Those that involve metals as a structural component do so either for catalytic capability, for redox potential, or to confer steric arrangements necessary to protein function. Metals can cause toxicity via substitution reactions in which the native, essential metal is displaced/replaced by another metal. In some cases, the enzyme can still function after such a displacement reaction. More often, however, enzyme function is diminished or completely abolished. For example, Cd can substitute for Zn in the protein famesyl protein transferase, an important enzyme in adding famesyl groups to proteins such as Ras. In this case, Cd diminishes the activity of the protein by 50%. Pb can substitute for Zn in 8-aminolevulinic acid dehydratase (ALAD), and it causes inhibition in vivo and in vitro. ALAD contains eight subunits, each of which requires Zn. Another classic example of metal ions substituting for other metal ions is Pb substitution for Ca in bones. 

Biomarkers are related to different toxicants and organizational levels. Several examples are given in Table 9.12. Biomarkers range from those that are highly specific to those that are non-specific (a) those highly specific, as the enzyme aminolevulinic acid dehydratase (ALAD), which catalyzes a reaction involved in heme synthesis and is very sensitive to inhibition by inorganic lead (b) those non-specific, as effects in the immune system that can be caused by a wide variety of pollutants. 

Figure 3 The synthesis of heme from glycine and sucdnyl-CoA. The enzymes are ALAS, S-aminolevulinic acid (ALA) synthase ALAD, S-aminolevulinic acid dehydratase PBGD, porphobilinogen deaminase UROIIIS, uroporphyrinogen III synthase UROD, uroporphyrinogen decarboxylase CPO, coproporphyrinogen oxidase PPO, protoporphyrinogen oxidase and FECH, ferrochelatase.

Burns CB, Godwin IR. 1991. A comparison of the effects of inorganic and alkyllead compounds on human erythrocytic delta-aminolevulinic-acid dehydratase (ALAD) activity in vitro. J Appl Toxicol 11 103-111. 

The genes for all the enzymes of human heme biosynthesis have been characterized (Table 32-2), and the structures of 5-aminolevulinic acid dehydratase (ALAD), hydroxymethyl-bilane synthase (HMBS), uroporphyrinogen-III synthase (UROS), uroporphyrinogen decarboxylase (UROD), and ferrochelatase (FECH) have been determined by x-ray crys-tallography. - - ... 

The therapeutic efficacy of oral administration of seed powder of M. oleifera (500 mg/kg, orally, once daily) post arsenic exposure (100 ppm in drinking water for 4 months) in rats has been investigated (49). Animals exposed to arsenic(lll) shows a significant inhibition of 8-aminolevulinic acid dehydratase (ALAD) activity, decrease in reduced glutathione (GSH) level and an increase in reactive oxygen species (ROS) in blood. On the other hand, a significant decrease in hepatic ALAD, and an increase in 8-aminolevulinic acid synthetase (ALAS) activity is observed after arsenic exposure. These changes... 

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). 

At one end of the spectrum the enzyme aminolevulinic acid dehydratase (ALAD) is highly specific, being inhibited only by lead. At the other end, mixed function oxydase enzymes and stress proteins are induced by many different classes of chemicals. Both specific and nonspecific biomarkers have their place in environmental assessments. A nonspecific biomarker can tell one that a pollutant is present in a meaningful concentration but does not tell one which chemical is present. Based on this information, a more detailed chemical investigation can be justified. In contrast, a specific biomarker tells one which chemical is present, but gives no information on the presence of other pollutants. 

Beegdahl 1A, Geubb A, Schutz A, Desnick RJ, Wetmue JG, Sassa S and Skeeeving S (1997). Lead-binding to d-aminolevulinic acid dehydratase (ALAD) in human erythrocytes. Pharmacol Toxicol 81 153-158. 

Rainbo v trout exposed to supernatant waste developed general stress symptoms at 13-15 °C, and plasma hypocalcemia and sex-dependent inhibition of erythrocytic delta-aminolevulinic acid dehydratase (ALAD) enzyme activity at 7-8°C (Lehtinen etal. 1984). 

ALA aminolevulinic acid ALAD 5-(5)aminolevulic acid dehydratase, an enzyme which is involved in the biosynthesis of the hemin-porphyrin skeleton decrease in its activity is monitored, e.g. in the case of increased exposure to lead albumin a group of proteins found in nearly every animal and in many vegetable tissues, e.g. semm albumin albuminuria increased excretion of albumin in the urine can indicate damage to the kidney... 

Several other classes of proteins have also been implicated as possible targets for lead, including other proteins in the heme biosynthetic pathway, leadbinding proteins in the kidney and brain, and heat shock proteins (342, 500-502). Lead is known to affect several steps in the heme biosynthetic pathway other than that catalyzed by ALAD Other profound effects include stimulation of 5-aminolevulinic acid synthase (ALAS) and decreased levels of iron incorporation into protoporphyrin by ferrochelatase (see Section VI.E.2 and Fig. 34) (10, 503-505). However, not all of these effects are due to direct interactions between lead and enzymes in the heme biosynthetic pathway. For instance, the widespread assertion that lead inhibits ferrochelatase is not supported by studies on the isolated enzyme (506, 507). Furthermore, increased levels of both erythrocyte protoporphyrin IX (EP) and zinc protoporphyrin (ZPP) are observed at high BLLs, suggesting that ferrochelatase is stiU competent to insert zinc into EP and that the increased levels of EP and ZPP associated with lead poisoning are most likely caused by lead interfering with iron uptake or transport (see Sections VI.C.4 and VI.E) (10, 506, 507). 

PBS Porphobilinogen synthase, also known as 5-aminolevulinic acid dehydratase, ALAD... 

Figure 17. Lead has been used as a heavy atom derivative to solve the phase problem in the crystal structures of a variety of protein including the calcium proteins calmodulin and synaptotagmin and die zinc protein 5-aminolevulinic acid dehydratase, ALAD. These structures provide useful insights into the coordination environments preferred by lead, which can bind both to carboxylate-rich calcium sites and thiol-rich zinc sites. Structures downloaded from die protein databank (3CLN, IRSY, 1AW5, IQNV) where necessary, lead was added to die figure based upon coordinates provided by the authors (240, 241, 243, 246). Figure adapted from Curr. Opin. Chem. Biol., Vol. 5, H.A. Godwin, The biological chemistry of lead, pp. 223-227, Copyright 2(X)1, with permission from Elsevier Science.

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