Delta-aminolevulinate Dehydrase Research Articles

The decrease in uroporphyrinogen decarboxylase activity induced by ethanol predisposes rats to the development of porphyria and accelerates xenobiotic-triggered porphyria, regardless of hepatic damage.

We evaluated the porphyrinogenic ability of ethanol (20% in drinking water) per se, its effect on the development of sporadic porphyria cutanea tarda induced by hexachlorobenzene in female Wistar rats (170-190 g, N = 8/group), and the relationship with hepatic damage. Twenty-five percent of the animals receiving ethanol increased up to 14-, 25-, and 4.5-fold the urinary excretion of delta-aminolevulinate, porphobilinogen, and porphyrins, respectively. Ethanol exacerbated the precursor excretions elicited by hexachlorobenzene. Hepatic porphyrin levels increased by hexachlorobenzene treatment, while this parameter only increased (up to 90-fold) in some of the animals that received ethanol alone. Ethanol reduced the activities of uroporphyrinogen decarboxylase, delta-aminolevulinate dehydrase and ferrochelatase. In the ethanol group, many of the animals showed a 30% decrease in uroporphyrinogen activity; in the ethanol + hexachlorobenzene group, this decrease occurred before the one caused by hexachlorobenzene alone. Ethanol exacerbated the effects of hexachlorobenzene, among others, on the rate-limiting enzyme delta-aminolevulinate synthetase. The plasma activities of enzymes that are markers of hepatic damage were similar in all drug-treated groups. These results indicate that 1) ethanol exacerbates the biochemical manifestation of sporadic hexachlorobenzene-induced porphyria cutanea tarda; 2) ethanol per se affects several enzymatic and excretion parameters of the heme metabolic pathway; 3) since not all the animals were affected to the same extent, ethanol seems to be a porphyrinogenic agent only when there is a predisposition, and 4) hepatic damage showed no correlation with the development of porphyria cutanea tarda.

Heme Biosynthesis by the Malarial Parasite: IMPORT OF δ-AMINOLEVULINATE DEHYDRASE FROM THE HOST RED CELL

The mouse and human malarial parasites, Plasmodium berghei and Plasmodium falciparum, respectively, synthesize heme de novo following the standard pathway observed in animals despite the availability of large amounts of heme, derived from red cell hemoglobin, which is stored as hemozoin pigment. The enzymes, delta-aminolevulinate dehydrase (ALAD), coproporphyrinogen oxidase, and ferrochelatase are present at strikingly high levels in the P. berghei infected mouse red cell in vivo. The isolated parasite has low levels of ALAD and the data clearly indicate it to be of red cell origin. The purified enzyme preparations from the uninfected red cell and the parasite are identical in kinetic properties, subunit molecular weight, cross-reaction with antibodies to the human enzyme, and N-terminal amino acid sequence. Immunogold electron microscopy of the infected culture indicates that the enzyme is present inside the parasite and, therefore, is not a contaminant. The parasite derives functional ALAD from the host and the enzyme binds specifically to isolated parasite membrane in vitro, suggestive of the involvement of a receptor in its translocation into the parasite. While, ALAD, coproporphyrinogen oxidase, and ferrochelatase from the parasite and the uninfected red cell supernatant have identical subunit molecular weights on SDS-polyacrylamide gel electrophoresis and show immunological cross-reaction with antibodies to the human enzymes, as revealed by Western analysis, the first enzyme of the pathway, namely, delta-aminolevulinate synthase (ALAS) in the parasite, unlike that of the red cell host, does not cross-react with antibodies to the human enzyme. However, ALAS enzyme activity in the parasite is higher than that of the infected red cell supernatant. We therefore conclude that the parasite, while making its own ALAS, imports ALAD and perhaps most of the other enzymes of the pathway from the host to synthesize heme de novo, and this would enable it to segregate this heme from the heme derived from red cell hemoglobin degradation. ALAS of the parasite and the receptor(s) involved in the translocation of the host enzymes into the parasite would be unique drug targets.

The contribution of sex, electrophoretic phenotype, pregnancy and race to the variability of delta-aminolevulinate dehydrase (ALADH) levels in human erythrocytes. A study in Black mixed Brazilians

The contribution of sex, electrophoretic phenotype, pregnancy and race to the variability of delta-aminolevulinate dehydrase (ALADH) levels in human erythrocytes. A study in Black mixed Brazilians

Genetic polymorphism of delta-aminolevulinate dehydrase in several population groups in Israel.

The genetic polymorphism of red cell delta aminolevulinate dehydrase (ALADH) has been investigated in several population groups in Israel: Ashkenazi Jews, non-Ashkenazi Jews from North Africa, Egypt, Turkey, Iraq, Iran, Yemen and the Balkans, and Arabs. The distribution of the ALADH genes was not homogeneous (chi 2 = 36.83; d.f. = 8; p less than 0.0005). A significantly higher frequency of the ALADH2 gene was observed among the Ashkenazi Jews (0.2021) than among the non-Ashkenazi Jews and Arabs (gene frequencies 0.0825-0.1290) or all the other population samples so far studied (Liberia, Japan, Italy, Germany and Spain).

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.

Assignment of the human gene for delta aminolevulinate dehydrase to chromosome 9 by somatic cell hybridization and specific enzyme immunoassay.

A non-competitive enzyme immunoassay specific for delta aminolevulinate dehydrase has been devised and applied to rodent-human hybrid cell lines. Two different conditions have been used, one specific for the human enzyme and the other indicative of both rodent and human enzymes. The ratio of the values obtained under the two conditions was used to discriminate between positive and negative clones. By this method the gene for ALA dehydrase has been assigned to chromosome 9.

Purification and properties of delta-aminolevulinate dehydrase from human erythrocytes.

Purification and properties of delta-aminolevulinate dehydrase from human erythrocytes.