Aminolevulinic acid dehydratase

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

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. 

Haeger-Aronsen B, Schutz A, Abdulla M. 1976. Antagonistic effect in vivo of zinc on inhibition of 8-aminolevulinic acid dehydratase by lead. Arch Environ Health 31 215-220. 

Lead (soft, Pb2+) Injuries to peripheral nervous system, disturbs heme synthesis and affects kidneys Pb2+ may replace Ca2+ with loss of functional and structural integrity. Reacts with sulfhydryl groups, replaces Zn2+ in 8-aminolevulinic acid dehydratase. 

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. 

A second major lead-induced toxicity involves interruption of heme synthesis. Lead interacts at several steps in the heme biosynthetic pathway (Figure 21.13). As mentioned above, Pb inhibits the enzyme 8-aminolevulinic acid dehydratase (ALA-D), which catalyzes the second step of heme synthesis involving the condensation of two molecules of aminolevulinic acid (ALA) to form porphobilinogen. The result of this inhibition is the accumulation of aminolevulinic acid in the serum and increased excretion of ALA in the urine. A second major disruption of the heme biosynthetic pathway is Pb inhibition of ferrochelatase. This enzyme is responsible for the incorporation of the ferrous ion (Fe2+) into protoporphrin IX to produce heme (Figure 21.2). Accumulated protoporphrin is incorporated into red blood cells and chelates zinc as the cells circulate. This zinc-protoporphrin complex is fluorescent and used to diagnose Pb poisoning. 

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). 

Meredith, PA. Moore, MR. Goldberg, A. Erythrocyte 8-aminolevulinic acid dehydratase activity and blood Protoporphyrin concentrations as indices of lead exposme and altered haem biosynthesis. Clin. Sci 1979 56 61-69. 

Lee, B.-K., Lee, G.-S., Stewart, F.S., Ahn, K.-D., Simon, D., Kelsey, K.T., et al., 2001. Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and 8-aminolevulinic acid dehydratase genes. Environ. Health Perspect. 109, 383—389. 

Dorward, A., Yagminas, A.P., 1994. Activity of erythrocyte 8-aminolevulinic acid dehydratase in the female cynomolgus monkey (Macaca fascicularis)-. kinetic analysis in control and lead-exposed animals. Comp. Biochem. Physiol. B. Biochem. Mol. Biol. 108, 241—252. 

Kelada, S.N., Shelton, E., Kaufmann, R.B., Khoury, M.J., 2001. 8-Aminolevulinic acid dehydratase genotype and lead toxicity a HuGE review. Am. J. Epidemiol. 154, 1—13. 

Scheuhammer, A.M., 1987. Erythrocyte 8-aminolevulinic acid dehydratase in birds. II. The effects of lead exposure in vivo. Toxicology 45, 165-175. 

Duydu, Y., Silzen, H.S., 2003. Influence of 8-aminolevulinic acid dehydratase (ALAD) polymorphism on the frequency of sister chromatid exchange (SCE) and the number of high-frequency cells (HFCs) in lymphocytes from lead-exposed workers. Mutat. Res. 540, 79-88. 

Bergdahl, I.A., Grubb, A., Schiitz, A., Desnick, RJ., Wetmur, J.G., Sassa, S., et al., 1997b. Lead binding to 8-aminolevulinic acid dehydratase (ALAD) in human erythrocytes. PharmacoL Toxicol. 81, 153—158. 

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