Inhibition of δ-aminolevulinic acid dehydratase by trichloroethylene

Fujita, Hideaki; Sadamoto, Tetsuo; Yamamoto, Masayuki; Kumai, Miho; Ikeda, Masayuki

doi:10.1016/0300-483x(84)90120-3

Cited by 10 publications

(4 citation statements)

References 31 publications

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“…An increase in the degradation rate may be due to iron-catalyzed oxidative damage to the enzyme. A somewhat analogous proposal was recently made to account for depression of ALA dehydrase in rats following treatment with halogenated hydrocarbons (34,35). The dehydrase may be particularly susceptible to damaging effects of a number of oxidizing reactive intermediates.…”

Section: Discussionmentioning

confidence: 82%

Hepatic heme synthesis in a new model of experimental hemochromatosis: Studies in rats fed finely divided elemental iron

et al. 1987

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Rats fed chow containing finely divided elemental iron (from carbonyl-iron) develop hepatic iron overload resembling human hereditary hemochromatosis in that deposition of iron is primarily in periportal hepatocytes and with hepatic iron concentrations sufficiently high to be associated in the human disease with hepatic fibrosis or cirrhosis. In recent studies using this model, we reported changes in hepatic hemoproteins and heme oxygenase, the rate-controlling enzyme of heme breakdown. We now report effects of iron-loading on three enzymes of heme synthesis: 5-aminolevulinate synthase; the first and rate-controlling enzyme of the pathway, 5-aminolevulinate dehydrase (or porphobilinogen synthase), and uroporphyrinogen decarboxylase, the activity of which is decreased in porphyria cutanea tarda, a liver disease in which iron is known to play an important but still poorly understood role. Of the three enzymes, only activity of the dehydrase was altered by iron-loading: it was decreased significantly as early as 1 week after starting iron feeding, and with marked iron overload was 30 to 32% of control values. The degree of decrease was inversely related (r = -0.77 to -0.88) to the degree of iron overload and was partially reversed within 1 to 3 days when feeding of the iron-supplemented diet was stopped. The decrease in dehydrase activity was not attributable to lack of reduced glutathione or other disulfide-reducing agents or to zinc deficiency; nor was evidence found for inhibition by iron compounds or other possible inhibitors present in iron-loaded livers.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 82%

Hepatic heme synthesis in a new model of experimental hemochromatosis: Studies in rats fed finely divided elemental iron

et al. 1987

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“…The changes were not considered to be toxicologically significant, since they were not dose-related and were within normal values for mice. Various hematological effects have been reported in other animal studies (Fujita et al, 1984;Koizumi et al, 1984;Goel et al, 1992), but since the hemoglobin concentration in erythrocytes did not change, the changes were not considered to be adverse. Goel and coworkers (1992) did, however, report a dose-related increase in cell density and related parameters in bone marrow in mice.…”

Section: Ethanol Consumptionmentioning

confidence: 91%

Trichloroethylene — a Review of the Literature From a Health Effects Perspective

Gist

Burg

1995

Toxicol Ind Health

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This report reviews the literature on the impact of exposure to trichloroethylene (TCE) on human health. Special emphasis is given to the health effects reported in excess of national norms by participants in the TCE Subregistry of the Volatile Organic Compounds Registry of the National Exposure Registries--persons with documented exposure to TCE through drinking and use of contaminated water. The health effects reported in excess by some or all of the sex and age groups studied were speech and hearing impairments, effects of stroke, liver problems, anemia and other blood disorders, diabetes, kidney disease, urinary tract disorders, and skin rashes.

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“…8 If these individuals are heterozygous carriers of ALAD deficiency, the prevalence of this condition is about 2% in a normal population. Clinical implications of these findings are obvious in that these individuals with low ALAD activity may be more vulnerable than normal subjects to toxic effects of chemicals or compounds such as lead, 14,15 trichloroethylene, 16 styrene oxide, 17 or bromobenzene, 18 which inhibit ALAD activity. 19 It is thus important to identify heterozygous carriers of ALAD deficiency and to define the nature of their enzymatic defect.…”

Section: Introductionmentioning

confidence: 99%

Highly heterogeneous nature of δ-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria

Maruno

Furuyama

Akagi

et al. 2001

Blood

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The properties of 9 ␦-aminolevulinate dehydratase (ALAD) mutants from patients with ALAD porphyria (ADP) were examined by bacterial expression of their complementary DNAs and by enzymologic and immunologic assays. ALADs were expressed as glutathione-S-transferase (GST) fusion proteins in Escherichia coli and purified by glutathioneaffinity column chromatography. The GST-ALAD fusion proteins were recognized by anti-ALAD antibodies and were enzymatically active as ALAD. The enzymatic activities of 3 ALAD mutants, K59N, A274T, and V153M, were 69.9%, 19.3%, and 41.0% of that of the wild-type ALAD, respectively, whereas 6 mutants, G133R, K59N/G133R, F12L, R240W, V275M, and delTC, showed little activity (< 8%). These variations generally reflect the phenotype of ALAD in vivo in patients with ADP and indicate that GST-ALAD fusion protein is indeed useful for predicting of the phenotype of ALAD mutants. The location of F12L mutation in the enzyme's molecular structure indicates that its disturbance of the quaternary contact of the ALAD dimer appears to have a significant influence on the enzymatic activity. Mouse monoclonal antibodies to human ALAD were developed that specifically recognized a carboxy terminal portion of ALAD, or other regions in the enzyme. This study represents the first complete analysis of 9 mutants of ALAD identified in ADP and indicates the highly heterogeneous nature of mutations in this disorder. IntroductionDelta-aminolevulinate dehydratase (ALAD) deficiency porphyria (ADP) is an autosomal recessive disorder caused by a homozygous ALAD deficiency. Patients with this condition have clinical symptoms of acute hepatic porphyria such as abdominal pain, vomiting, pain in the arms and legs, and neuropathy. ALAD is the second enzyme in the heme biosynthetic pathway. It catalyzes the Knorr-type condensation of 2 molecules of aminolevulinate acid (ALA) to form a monopyrrole, porphobilinogen (PBG). 1 This enzyme activity is present in large excess compared to other enzymes in the heme biosynthetic pathway, and its partial deficiency does not usually result in any clinical consequences. Seven patients with ADP have been reported to date, 2-6 though only 4 of them have been confirmed by immunochemical or molecular analysis. [2][3][4] Of these 4 cases, the first 2 were German patients reported by Doss and coworkers, 7 the third was a Swedish baby boy studied by Thunell and colleagues, 8 and the fourth was an elderly Belgian man reported by Hassoun and associates. 9 Recently, an asymptomatic Swedish baby girl has been identified to have a markedly decreased ALAD activity. 10 Thus far, a total of 9 point mutations of the alad gene have been identified in these 5 subjects, which resulted in different amino acid changes. However, the enzymatic activity of ALAD expressed by mutant ALAD was investigated only for 4 mutants, A274T and R240W, in German patient B, 3 and V153M and delTC in German patient H 11 (singleletter amino acid codes). This previous study with German patient B demonstrated that ALAD activity co...

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Inhibition of δ-aminolevulinic acid dehydratase by trichloroethylene

Cited by 10 publications

References 31 publications

Hepatic heme synthesis in a new model of experimental hemochromatosis: Studies in rats fed finely divided elemental iron

Hepatic heme synthesis in a new model of experimental hemochromatosis: Studies in rats fed finely divided elemental iron

Trichloroethylene — a Review of the Literature From a Health Effects Perspective

Highly heterogeneous nature of δ-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria

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