The protective effect of delta-aminolevulinic acid dehydratase 1-2 and 2-2 isozymes against blood lead with higher hematologic parameters.

Previous studies have suggested that delta-aminolevulinic acid dehydratase (ALAD) types 1-2 or 2-2 are protective against the toxicity of blood lead (PbB) when zinc protoporphyrin (ZPP) levels are low because of differential binding of lead in erythrocytes. The hypothesis is that subjects with the ALAD 1-1 genotype are more susceptible to lead exposure with impaired hematologic synthesis and therefore that iron nutrition is more important in those with the ALAD 1-1 genotype. The purpose of this study was to prove the protective effect of ALAD 1-2/2-2 against PbB with higher hematologic parameters. Data on 1,219 male workers from eight lead-using factories in the Republic of Korea were examined in this cross-sectional study. Blood samples were evaluated for PbB, ZPP, hemoglobin (Hb), and serum iron (SFe) concentrations and ALAD genotypes. The overall prevalence of the ALAD 1-2/2-2 genotype was 9.3%, which was associated with lower log ZPP (p < 0.001) and higher Hb (p = 0.014) levels. For the subjects with normal iron status (SFe levels > 60 micro g/dL), those with the ALAD 1-1 genotype were more likely to be anemic (adjusted odds ratio of 5.2; 95% confidence interval, 1.2-22.6) than those with ALAD 1-2/2-2. The study confirms the protective effects of ALAD 1-2/2-2 polymorphisms against PbB on hematologic pathways. In order to promote health and to minimize the toxicity of lead exposure more effectively, the nutritional management of iron in Korean workers should take both their ALAD genotypes and occupational lead exposures into account.

Hemoglobin content is increased in the human erythroleukemia K562 cell line by a 56.2-kD peptide from uremic plasma.

BACKGROUND: Some abnormalities in porphyrin metabolism have been described in erythrocytes from patients with end-stage renal failure. A peptidic fraction of 56.2 kD isolated from plasma of these patients was previously identified as an aminolevulinate dehydratase inhibitor. The aim of this study was to examine the in vitro effect of this peptide on heme synthesis in the erythroleukemia K562 cells. METHODS: The 56.2-kD fraction was purified from uremic plasma by protein electroelution and, its action on the mitochondrial rate-limiting steps of heme synthesis, as well as the hemoglobin content during erythroid differentiation induced by sodium butyrate, was investigated in K562 cells. RESULTS: Two hours after addition of the 56.2-kD peptide, the activities of aminolevulinate acid synthase and aminolevulinate dehydratase were reduced while the activity of the ferrochelatase was enhanced, indicating that this peptide easily across the membranes. A 3-day incubation with this peptide enhanced approximately twofold the hemoglobin and porphyrin levels during erythroid differentiation of K562 cells without variation of cell growth. CONCLUSION: This study shows that the addition of the 56.2-kD uremic factor to K562 cells was clearly implicated in heme disturbances existing in chronic renal failure but it did not play a negative role in the pathogenesis of the uremic anemia.

Processing of an apicoplast leader sequence in Plasmodium falciparum and the identification of a putative leader cleavage enzyme.

The plastid (apicoplast) of the malaria-causing parasite Plasmodium falciparum was derived via a secondary endosymbiotic process. As in other secondary endosymbionts, numerous genes for apicoplast proteins are located in the nucleus, and the encoded proteins are targeted to the organelle courtesy of a bipartite N-terminal extension. The first part of this leader sequence is a signal peptide that targets proteins to the secretory pathway. The second, so-called transit peptide region is required to direct proteins from the secretory pathway across the multiple membranes surrounding the apicoplast. In this paper we perform a pulse-chase experiment and N-terminal sequencing to show that the transit peptide of an apicoplast-targeted protein is cleaved, presumably upon import of the protein into the apicoplast. We identify a gene whose product likely performs this cleavage reaction, namely a stromal-processing peptidase (SPP) homologue. In plants SPP cleaves the transit peptides of plastid-targeted proteins. The P. falciparum SPP homologue contains a bipartite N-terminal apicoplast-targeting leader. Interestingly, it shares this leader sequence with a Delta-aminolevulinic acid dehydratase homologue via an alternative splicing event.

Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and delta-aminolevulinic acid dehydratase genes.

Evidence suggests that lead and selected genes known to modify the toxicokinetics of lead--namely, those for the vitamin D receptor (VDR) and delta-aminolevulinic acid dehydratase (ALAD)--may independently influence blood pressure and hypertension risk. We report the relations among ALAD and VDR genotypes, three lead dose measures, and blood pressure and hypertension status in 798 Korean lead workers and 135 controls without occupational exposure to lead. Lead dose was assessed by blood lead, tibia lead measured by X-ray fluorescence, and dimercaptosuccinic acid (DMSA)-chelatable lead. Among lead workers, 9.9% (n = 79) were heterozygous for the ALAD(2) allele, and there were no ALAD(2) homozygotes; 11.2% (n = 89) had at least one copy of the VDR B allele, and 0.5% (n = 4) had the BB genotype. In linear regression models to control for covariates, VDR genotype (BB and Bb vs. bb), blood lead, tibia lead, and DMSA-chelatable lead were all positive predictors of systolic blood pressure. On average, lead workers with the VDR B allele, mainly heterozygotes, had systolic blood pressures that were 2.7-3.7 mm Hg higher than did workers with the bb genotype. VDR genotype was also associated with diastolic blood pressure; on average, lead workers with the VDR B allele had diastolic blood pressures that were 1.9-2.5 mm Hg higher than did lead workers with the VDR bb genotype (p = 0.04). VDR genotype modified the relation of age with systolic blood pressure; compared to lead workers with the VDR bb genotype, workers with the VDR B allele had larger elevations in blood pressure with increasing age. Lead workers with the VDR B allele also had a higher prevalence of hypertension compared to lead workers with the bb genotype [adjusted odds ratio (95% confidence interval) = 2.1 (1.0, 4.4), p = 0.05]. None of the lead biomarkers was associated with diastolic blood pressure, and tibia lead was the only lead dose measure that was a significant predictor of hypertension status. In contrast to VDR, ALAD genotype was not associated with the blood pressure measures and did not modify associations of the lead dose measures with any of the blood pressure measures. To our knowledge, these are the first data to suggest that the common genetic polymorphism in the VDR is associated with blood pressure and hypertension risk. We speculate that the BsmI polymorphism may be in linkage disequilibrium with another functional variant at the VDR locus or with a nearby gene.

Regulation of porphyrin and heme metabolism in the kidney.

Heme biosynthetic capacity within the kidney is localized mainly within the cells of the proximal convoluted tubule. Porphyrin accumulation in response to porphyrinogenic agents occurs predominantly in the cortical nephrons and decreases dramatically in the medullary region. This pattern of heme biosynthetic capacity correlates with the distribution of mixed function oxidase activities in the kidney. The regulation of heme biosynthesis in kidney cells is qualitatively comparable with that observed in liver, but differs with respect to the time required to realize induction of ALA synthetase in response to porphyrinogenic chemicals. This refractoriness may reflect a substantially greater ratio of regulatory or uncommitted heme to overall heme biosynthetic activity in renal cells, as compared with the hepatocyte. Studies on the mechanisms of trace metal-induced renal porphyria support the view that the kidney can play an important, even predominant, role in the etiology of excess urinary porphyrins excreted as a result of disordered porphyrin metabolism. Evidence from clinical studies suggests that the kidney may also play an important role in the etiology and manifestations of inherited and acquired forms of human porphyria.

S-adenosyl-L-methionine: its effect on aminolevulinate dehydratase and glutathione in acute ethanol intoxication.

The effect of disulfiram and S-adenosyl-L-methionine (SAM) administration to acute ethanol intoxicated mice on the hepatic glutathione (GSH) concentration and aminolevulinic and dehydratase (ALA-D) activity was investigated. It was found that both GSH levels and ALA-D activity were decreased, and evidence suggested that the toxic action of ethanol was due to its conversion into acetaldehyde. Administration of SAM reverses the effects of acute alcohol abuse by increasing liver GSH availability. In vitro, hepatic ALA-D activity was not modified by ethanol; instead it was non-competitively inhibited by acetaldehyde. This inhibition was efficiently reversed by GSH and cysteine (CySH). Therefore, a mechanism for the action of ethanol on ALA-D, based on the inhibitory effect of acetaldehyde, is proposed.