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Biomedical subjects

Y Nordmann

Publications and source records attributed to Y Nordmann.

At least 109 records · Page 6Linked to original sources
PubMed1987

Porphyria cutanea tarda and HLA-linked hemochromatosis. Evidence against a systematic association.

This study was designed to test the hypothesis that a hemochromatosis allele is implicated in the expression of porphyria cutanea tarda. HLA phenotypes were determined in 69 porphyria cutanea tarda patients, 42 of which had the sporadic type (normal erythrocyte uroporphyrinogen decarboxylase activity) and 27 unrelated patients who had the familial type (diminished erythrocyte uroporphyrinogen decarboxylase activity). The incidence of HLA antigen A3, a marker of the hemochromatosis allele, was identical in the sporadic patients (23.8%), in the familial patients (22.2%), and in the controls (24.5%). Furthermore, no clinical difference could be found between A3 and non-A3 patients. These results demonstrate no systematic association between hemochromatosis and porphyria cutanea tarda in the population studied. Another HLA-linked gene, however, could be implicated in the expression of the disease as HLA antigen DR7 presented an incidence statistically different (p less than 0.05) between sporadic (16.6%) and familial patients (43%).

Adult↗
PubMed1987

Homozygous variegate porphyria. A severe skin disease of infancy.

A boy exhibited severe bullous skin disease a few days after birth, followed by increased fragility of the exposed skin in spring and summer. Examination at 2 1/2 years of age led to characteristic biochemical findings: increased excretion of fecal porphyrins (coproporphyrin 121 to 131 and protoporphyrin 467 to 576 nmol/g dry weight), and increased erythrocyte protoporphyrin concentration (3643 to 4840 nmol/l). Lymphocyte protoporphyrinogen oxidase activity was very low in the patient (0.4 nmol/mg protein/h) and half-normal (2.7 and 2.3 nmol/mg protein/h) in the parents, suggesting that the patient had homozygous variegate porphyria. Severe skin symptoms and a high concentration of red cell protoporphyrin concentration in an infant should prompt suspicion of homozygous acute hepatic porphyria.

Acute Disease↗
PubMed1986

Uroporphyrinogen decarboxylase structural mutant (Gly281----Glu) in a case of porphyria.

Uroporphyrinogen decarboxylase deficiency in man is responsible for familial porphyria cutanea tarda and hepatoerythropoietic porphyria. A recent study of a family with hepatoerythropoietic porphyria showed that the enzyme defect resulted from rapid degradation of the protein in vivo. Cloning and sequencing of a complementary DNA for the mutated gene revealed that the mutation was due to the replacement of a glycine residue by a glutamic acid residue at position 281. This base change leads to a protein that is very rapidly degraded in the presence of cell lysate. Characterization of the mutation will allow comparison of this defect in a homozygous patient with defects in other patients with familial porphyria cutanea tarda.

Amino Acid Sequence↗
PubMed1986

[Acute attacks of hepatic porphyria. Treatment with hematin. 5 cases].

The effectiveness of 2 hematins administered by intravenous infusion was compared in acute intermittent porphyria. Judging from subjective symptoms (abdominal pain), clinical improvement was complete and constant. There was a rapid decrease in urinary excretion of porphyrins precursors, with a clearer response of delta-aminolevulinic acid than of porphobilinogen. Urine levels of uroporphyrin often returned to normal after two infusions. The drugs were very well tolerated. Provided it is administered early, before neurological complications develop, treatment with hematin completely relieves abdominal symptoms and suppresses most of the biochemical changes associated with hepatic porphyria.

Acute Disease↗
PubMed1986

Porphobilinogen deaminase is unstable in the absence of its substrate.

Porphobilinogen deaminase is induced during the dimethyl sulfoxide-mediated differentiation of Friend erythroleukemia cells. We have previously shown that when succinylacetone, a potent inhibitor of porphobilinogen formation, is present during the differentiation process, the induction of the enzyme is apparently suppressed. Here, we provide evidence that, in this condition, porphobilinogen deaminase is synthesized normally but does not accumulate as a consequence of an accelerated turnover. The normal half-life of the protein is 24 h but decreases to 10 h when the formation of its substrate is impaired by succinylacetone. We propose that when the enzyme is covalently bound to its substrate, a normal step in this enzymatic reaction, it is protected from proteolytic degradation, and we show that this new finding is relevant to the human disorder acute intermittent porphyria.

Ammonia-Lyases↗
PubMed1986

[Peridural anesthesia with procaine and fentanyl in a parturient with acute intermittent porphyria].

Acute intermittent porphyria is one of three severe hepatic porphyrias. Clinical manifestations include intermittent acute attacks of abdominal pain and neuropathy with an occasionally outcome. These attacks are often precipitated by endogenous (menstrual cycle and pregnancy in women) or exogenous factors (porphyrinogenic drugs). An epidural analgesia was performed during the labour of a pregnant woman with acute intermittent porphyria just after an acute attack of abdominal pain. Analgesia was obtained using procaine and fentanyl. The choice of drugs was based on available clinical reports and experimental studies of the porphyrinogenicity of drugs in animal models (rat in vivo and chick embryo in ovo).

Acute Disease↗
PubMed1986

Molecular analysis of uroporphyrinogen decarboxylase deficiency in a family with two cases of hepatoerythropoietic porphyria.

In order to determine the molecular basis of uroporphyrinogen (URO) decarboxylase deficiency responsible for hepatoerythropoietic porphyria (HEP) and familial porphyria cutanea tarda, we used a human URO decarboxylase cDNA to analyze the organization and expression of the URO decarboxylase gene in lymphoblastoid cells from normal individuals and from two patients with HEP. We could detect neither deletions nor rearrangements in the URO decarboxylase gene. Synthesis, processing, and cell-free translation of the specific transcripts appeared to be normal. The half-life of the abnormal protein was 12 times shorter than that of the normal enzyme. The results indicate that the enzyme defect is due to a rapid degradation of the protein in vivo. This study is the first to provide information regarding the molecular mechanism responsible for the URO decarboxylase deficiency in HEP.

Carboxy-Lyases↗
PubMed1986

Depletion of histidine and tryptophan serum levels in porphyria cutanea tarda and congenital erythropoietic porphyria patients after irradiation with visible light.

We have studied the photosensitized oxidation, via singlet oxygen production, of histidine (His) and tryptophan (Trp) in the serum of porphyria patients and in the serum of healthy volunteers before or after addition of hematoporphyrin. It was observed that free plasma His and Trp are good probes of singlet oxygen production in the blood under visible light irradiation. However, Trp, which is mostly bound to serum albumin, is much less susceptible to photooxidation than His, which remains free in the plasma. These results must not be ignored in systemic effects of porphyrias and in photochemotherapy with hematoporphyrin derivatives.

Blood↗
PubMed1985

Accumulation of porphobilinogen deaminase, uroporphyrinogen decarboxylase, and alpha- and beta-globin mRNAs during differentiation of mouse erythroleukemic cells. Effects of succinylacetone.

We have monitored, during the dimethyl sulfoxide (Me2SO)-induced differentiation of MEL cells, the accumulation of mRNAs encoding two enzymes of the heme biosynthetic pathway, namely porphobilinogen deaminase and uroporphyrinogen decarboxylase. Our results demonstrate that the induction of these two enzymes is accounted for by a coordinate increase in their corresponding mRNAs, as estimated by hybridization with specific cloned cDNA probes. These events occur early during the differentiation process and precede the accumulation of alpha- and beta-globin mRNAs. Blocking the heme biosynthetic pathway with succinylacetone does not appear to modify the Me2SO-mediated increase of porphobilinogen deaminase and uroporphyrinogen decarboxylase mRNAs although succinylacetone has been shown to prevent the induction of immunoreactive porphobilinogen deaminase as well as its enzymatic activity (Beaumont, C., Deybach, J. C., Grandchamp, B., Da Silva, V., de Verneuil, H., and Nordmann, Y. (1984) Exp. Cell Res. 154, 474-484). Heme depletion resulting from the presence of succinylacetone in the culture medium reduces the extent of the Me2SO-mediated accumulation of alpha- and beta-globin mRNAs, and this effect is reversed by the addition of 10 microM exogenous hemin. Although the presence of succinylacetone prevents hemoglobinization of MEL cells, it does not prevent MEL cells from losing their proliferative capacity when treated with Me2SO.

Ammonia-Lyases↗
PubMed1985

The mitochondrial location of protoporphyrinogen oxidase.

Using the digitonin method and subsequent fractionation of rat liver mitochondria, protoporphyrinogen oxidase (penultimate enzyme in the heme biosynthesis pathway) was found to be closely associated with the mitochondrial inner membrane fraction. Chemical treatment with non-specific probes (trypsin and diazobenzene sulfonate) of either intact or inverted mitoplasts, indicated that protoporphyrinogen oxidase was anchored within the lipid bilayer of the inner membrane. Protoporphyrinogen had an equal access to the active site of the enzyme from both sides of the inner membrane and its transformation to protoporphyrin did not appear to be energy-dependent. Studies of protoporphyrinogen synthesis from exogenously added coproporphyrinogen in either intact or hypoosmotically treated mitochondria underlined the importance of the peculiar submitochondrial location of coproporphyrinogen oxidase and protoporphyrinogen oxidase for the transfer of substrates to the inner membrane.

Animals↗
PubMed1985

Hereditary hepatic porphyria with delta aminolevulinate dehydrase deficiency: immunologic characterization of the non-catalytic enzyme.

Immunoreactive delta-aminolevulinate dehydrase (ALA-D) was measured in lysates from two porphyric patients with ALA-D deficiency (enzyme activities were below 2% of the normal level). By using two different immunologic methods, we found a cross-reactive immunologic material (CRIM+) which corresponded to 20% and 33% of the control level. Therefore the molecular basis that accounts for the deficiency of ALA-D in these patients is a structurally modified enzyme. The methods used to determine the molecular weight (by Western blotting) and the isoelectric point (by chromatofocusing) of the mutants did not show any difference by comparison with the normal enzyme.

Electrophoresis, Polyacrylamide Gel↗
PubMed1984

[Detection of chronic lead poisoning. Value of the assay of erythrocyte protoporphyrin].

The most common screening tests for lead poisoning are reviewed. Stippled red cells are inconstant and appear too late. Blood lead concentrations are difficult to measure accurately and often are uncorrelated with body lead stores. Excess of delta aminolevulinic acid and coproporphyrin in urine does not appear early enough. A marked increase of erythrocyte protoporphyrin level practically clinches the diagnosis, later confirmed by increase of lead in urine after an EDTA lead-mobilization test. Measurements of erythrocyte protoporphyrin levels are easy to perform, more sensitive, more precocious and cheaper than the other methods, but their relative lack of specificity must be borne in mind.

5'-Nucleotidase↗
PubMed1984

Cell-free translation of human uroporphyrinogen decarboxylase mRNAs.

Uroporphyrinogen decarboxylase was synthesized in a reticulocyte lysate cell-free system under the direction of messenger RNAs isolated from human fetal liver and from human reticulocytes. The enzyme was specifically isolated by immuno affinity chromatography. Analysis of the translation products showed that uroporphyrinogen decarboxylase was synthesized in vitro with its mature molecular weight. This enzyme represented 0.04% of the total neosynthesized proteins under the direction of fetal liver mRNA and about ten times less (0.005%) with reticulocyte mRNA.

Anemia, Sickle Cell↗