Inhibition of δ-Aminolevulinic Acid Dehydrase by δ-Oximinolevulinic Acid

Tschudy, Donald P.; Collins, Annie; Caughey, Winslow S.; Kleinspehn, George G.

doi:10.1126/science.131.3410.1380

Cited by 29 publications

(37 citation statements)

References 2 publications

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“…The evidence of a role for a short-living haem protein operating as oxygen sensor in the control of EPO gene expression in primary cultures of hepatocytes was found to be less conclusive than reported by Goldberg et al for hepatoma cells [14]. As reported in Hep 3B cells, cycloheximide, dioxoheptanoic acid and desferrioxamine, substances proposed to interfere with the synthesis of such a haem protein [14,35,40] inhibited the hypoxia-induced increases in EPO mRNA levels of isolated hepatocytes (Fig. 6).…”

Section: Discussionmentioning

confidence: 61%

“…Under this condition, however, total RNA synthesis during the final 2.5 h of incubation, as assessed by [3H]uridine incorporation, was only 2 + 1% (mean + SE, n = 3) of the RNA synthesis in cultures kept at 3 % 02 in the absence of the drug. EPO mRNA accumulation was also inhibited in the presence of desferrioxamine (130 ~tM) (35% reduction), an iron chelator and inhibitor of haem synthesis [35] and dioxoheptanoic acid (2 mM) (79% reduction), an inhibitor of aminolaevulinate dehydratase [40]. During the final 2.5 h of incubation with these two compounds…”

Section: Epo Mrna Levels In Cultured Hepatocytesmentioning

confidence: 93%

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Oxygen-dependent expression of the erythropoietin gene in rat hepatocytes in vitro

et al. 1993

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Abstract. Since in juvenile rats the liver is the predominant site of erythropoietin (EPO) gene expression, we have used primary cultures of juvenile rat hepatocytes to establish an in vitro system for investigation of oxygendependent EPO formation. When isolated hepatocytes were incubated at reduced oxygen tensions for 18-48 h, we found increased secretion of EPO protein and elevated levels of EPO mRNA, as determined by RNase protection. This increase was maximal at 3% 02, where EPO mRNA levels after 18 h were approximately 15-fold higher than at 20% 02. The increase in EPO mRNA at low oxygen tensions was specific insofar as [3H]uridine incorporation, as a measure of total RNA synthesis, was reduced by approximately 50% at 3% 02, and it appeared to involve gene transcription since it was abolished in the presence of actinomycin D (35 taM). Significant increases in EPO mRNA were also observed in cells kept at 20% oxygen in the presence of cobalt chloride (50 pM) and nickel chloride (400 ~tM), but EPO mRNA levels achieved under these conditions were less than 7% of those in cells incubated at 3% oxygen. No increase in EPO mRNA levels was observed in cultures incubated at 20% 02 in the presence of cyclic dibutyryl-AMP (10 pM-3 raM), cyclic 8-bromoGMP (10 pM-1 raM), cyclohexyladenosine (1 ~tM), 5'-N-ethylcarboxamidoadenosine (1 gM) and phorbol 12-myristate 13-acetate (3 nM). In the presence of 10% carbon monoxide, used to block haem proteins in their oxy conformation, EPO mRNA levels in hepatocytes incubated at low oxygen tensions were reduced to 63%. Taken together, these findings indicate that oxygen-dependent control of the EPO gene in hepatocytes operates via intrinsic cellular oxygen-sensing mechanisms. Their signal transduction does not seem to occur via classical "second-messenger" pathways. A haem protein may be involved in oxygen sensing, but no conclusive evidence was obtained as to whether it is essential.Correspondence to: K.-U. Eckardt

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Section: Discussionmentioning

confidence: 61%

Section: Epo Mrna Levels In Cultured Hepatocytesmentioning

confidence: 93%

Oxygen-dependent expression of the erythropoietin gene in rat hepatocytes in vitro

et al. 1993

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“…Treatment with SA, a specific inhibitor of 5-aminolaevulinic acid dehydratase (Tschudy et al, 1981), caused a Ͼ50% reduction in heme synthesis (Chernova et al, 2006). Continuous treatment for Ͼ2 weeks created a chronic deficiency in the cortical culture that showed many changes consistent with neurite degeneration.…”

Section: Resultsmentioning

confidence: 99%

Neurite Degeneration Induced by Heme Deficiency Mediated via Inhibition of NMDA Receptor-Dependent Extracellular Signal-Regulated Kinase 1/2 Activation

Chernova¹,

Steinert²,

Guérin³

et al. 2007

J. Neurosci.

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The early stages of many neurodegenerative diseases and age-related degeneration are characterized by neurite damage and compromised synaptic function that precede neuronal cell death. We investigated the signaling mechanisms underlying neurite degeneration using cortical neuron cultures. Inhibition of heme synthesis caused neurite damage, without neuronal death, and was mediated by reduced NMDA receptor (NMDAR) expression and phosphorylation. The signaling toward the degenerative phenotype involved suppression of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, and electrophysiological recording showed that the neurodegeneration is accompanied by reduced NMDAR current and Ca 2ϩ influx, as well as reduced voltage-gated sodium currents, consistent with compromised neurite integrity. Rescue from the degenerative phenotype by heme replacement was dependent on restoration of NR2B subunit phosphorylation and expression of NMDAR currents with higher Ca 2ϩ permeability, consistent with triggering prosurvival ERK1/2 signaling to maintain and extend neurites. This study demonstrated a new mechanism of neurodegeneration in which impaired heme synthesis led to NMDAR signaling dysfunction, suppression of the prosurvival ERK1/2 pathway, and progressive fragmentation of neuronal projections.

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“…To test whether heme deficiency per se could effect neuronal gene expression, cells were treated continuously with succinyl acetone (SA), a specific inhibitor of ALA dehydratase (Tschudy et al, 1981), or NMP, a specific inhibitor of ferrochelatase (De Matteis and Marks, 1996). Heme synthesis in cultures was significantly depressed by both treatments (Fig.…”

Section: Senescence Of Primary Cortical Neuronsmentioning

confidence: 99%

Heme Deficiency Is Associated with Senescence and Causes Suppression ofN-Methyl-d-aspartate Receptor Subunits Expression in Primary Cortical Neurons

Chernova

Nicotera²,

Smith³

2005

Mol Pharmacol

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Heme is a crucial component of many pharmacological and toxicological processes, and studies have suggested that heme deficiency may play a role in cellular ageing. A model of ageing neurons was established using prolonged cultures of BALB/c mouse primary cortical neurons. Aged neurons displayed a senescent phenotype and a marked up-regulation of cathepsin-L expression. Down-regulation of the candidate neuronspecific genes for N-methyl-D-aspartate (NMDA) receptor subunits (NMDA1 and -⑀2) and neurofilament light peptide (NF-L) were found to be characteristic of the aging process as reported in vivo (Brain 40 -45, 2002). In contrast, the genes for the controlling enzymes of heme synthesis and degradation (5-aminolevulinate synthase 1 and heme oxygenase 1, respectively) were up-regulated, implying depletion of a regulatory heme pool. Inhibition of heme synthesis (by 70 -80%) at different enzymic steps by succinyl acetone and N-methylprotoporphyrin IX resulted in the earlier lowered expression of NMDA1 and -⑀2 and NF-L. Exogenous hemin added to heme-depleted cells rescued the expression of these neuron-specific genes. Culture of cortical neurons from BALB/c Fech m1Pas mutant mice demonstrating depressed heme synthesis showed premature senescence and reduced expression of NMDA1 and -⑀2 receptor subunits and NF-L compared with wild-type cells. Our findings suggest that reduced availability of heme in neurons associated with senescence may have significant effects on synaptic function.

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Inhibition of δ-Aminolevulinic Acid Dehydrase by δ-Oximinolevulinic Acid

Abstract: delta-Oximinolevulinic acid competitively inhibits delta-aminolevulinic acid dehydrase at low concentrations.

Cited by 29 publications

References 2 publications

Oxygen-dependent expression of the erythropoietin gene in rat hepatocytes in vitro

Oxygen-dependent expression of the erythropoietin gene in rat hepatocytes in vitro

Neurite Degeneration Induced by Heme Deficiency Mediated via Inhibition of NMDA Receptor-Dependent Extracellular Signal-Regulated Kinase 1/2 Activation

Heme Deficiency Is Associated with Senescence and Causes Suppression ofN-Methyl-d-aspartate Receptor Subunits Expression in Primary Cortical Neurons

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