Disease relevance of Alas1

• Increased pulmonary heme oxygenase-1 and delta-aminolevulinate synthase expression in monocrotaline-induced pulmonary hypertension [1].
• Tissue-specific gene expression of heme oxygenase-1 (HO-1) and non-specific delta-aminolevulinate synthase (ALAS-N) in a rat model of septic multiple organ dysfunction syndrome [2].
• A dose of 20 mg cimetidine/100 gm body weight resulted in a 50% decrease in the AIA-induced hepatic ALA-S activity compared to rats treated with AIA alone [3].
• Aging-related decreases in hepatic mitochondrial and cytosolic delta-aminolevulinic acid synthase during experimental porphyria [4].

High impact information on Alas1

• The method uses the synthetic metalloporphyrin cobalt-heme (cobalt protoporphyrin IX), which possesses the dual biological properties of repressing delta-aminolevulinate synthase, the rate-limiting enzyme of heme biosynthesis, and of potently inducing microsomal heme oxygenase, the rate-limiting enzyme of heme catabolism [5].
• In this study, cobalt was shown to block almost entirely the ability of the barbiturate analogue allylisopropylacetamide to induce delta-aminolevulinate synthase in liver [6].
• In this study, treatment with hydrocortisone prevented the exaggerated metal induction of heme oxygenase but did not affect the associated initial decline or the late rebound of delta-aminolevulinate synthase [7].
• Translocation of delta-aminolevulinate synthase from the cytosol to the mitochondria and its regulation by hemin in the rat liver [8].
• These studies report the effects of thyroid status on the activity of hepatic delta-aminolevulinate synthase (ALAS), the initial and rate-limiting enzyme in heme synthesis [9].

Chemical compound and disease context of Alas1

• Our findings indicate that chloroquine acts by reduction of the delta-aminolevulinate synthase activity, probably by influencing the regulation of the key enzyme of the heme biosynthesis, which is enhanced in human porphyria cutanea tarda, as well as in the HCB-induced porphyria of the rats [10].

Biological context of Alas1

• Paraquat-generated oxidative stress in rat liver induces heme oxygenase-1 and aminolevulinic acid synthase [11].
• Treatment of cells with LPS elicited an increase in HO-1 mRNA, accompanying down regulation of delta-aminolevulinate synthase, in a dose-dependent fashion [12].
• In this study, we examined changes in gene expression of HO-1 and non-specific delta-aminolevulinate synthase (ALAS-N) (EC 2.3.1.37), the rate-limiting enzymes in heme catabolism and heme synthesis, respectively, after intraperitoneal administration of bacterial lipopolysaccharide (LPS) to rats [2].
• Heme metabolism and erythropoiesis in abnormal iron states: role of delta-aminolevulinic acid synthase and heme oxygenase [13].
• These changes were also accompanied by inhibition of ALAD activity in kidney, delta-aminolevulinic acid synthase (ALAS) activities in liver and changes in platelet counts in whole blood suggesting disturbed haem synthesis pathway [14].

Anatomical context of Alas1

• Novel regulation of delta-aminolevulinate synthase in the rat harderian gland [15].
• Results indicate that the rate limiting enzymes delta-aminolevulinic acid synthase (ALAS) and heme oxygenase were significantly elevated in the iron-overloaded hepatic and bone marrow cells and near normal levels in cells from iron-deficient rats [13].
• Purification and some properties of delta-aminolevulinate synthase from the rat liver cytosol fraction and immunochemical identity of the cytosolic enzyme and the mitochondrial enzyme [16].
• When phenformin was added to isolated rat hepatocytes of normal rats, induction of ALA-S and ferrochelatase activities and cytochrome P-450 content was observed only in the presence of added dibutyryl cAMP [17].
• However, 5-aminolevulinic acid synthase activity is reduced by nearly 40% in Gunn rat liver mitochondria, thus explaining the reduced size of the hepatic heme pool [18].

Associations of Alas1 with chemical compounds

• We measured the half-life of the hepatic delta-aminolevulinate synthase mRNA by RNA blot hybridization analysis using allylisopropylacetamide-induced porphyric rats as an experimental model and the rat cDNA as a hybridization probe [19].
• In the kidney and liver ALA-D, delta-aminolevulinic acid synthase (ALA-S), and heme oxygenase activity were also determined [20].
• Our results revealed that gossypol stimulated the hepatic, splenic, and renal delta-aminolevulinic acid synthase (ALA-S) activity, the heme biosynthetic enzyme, and simultaneous administration of CrPP and gossypol synergized the gossypol-mediated increase of ALA-S activity [21].
• A rise in ALA-S activity seen after its early inhibition and its return to approximate control values after 60 min suggest a reversible inhibition of ALA-S by a metabolite of cimetidine and may correspond to its clearance from the animal [22].
• MEASUREMENTS AND MAIN RESULTS: Following lipopolysaccharide treatment, expression of heme oxygenase-1 and nonspecific delta-aminolevulinate synthase (ALAS-N), the rate-limiting enzymes of heme catabolism and biosynthesis, respectively, was examined in various regions of the intestine [23].

Other interactions of Alas1

• A model implicating a nuclear heme pool regulating the transcription of delta-aminolevulinate synthase, CYPIIB1/B2, and heme oxygenase genes is proposed [24].
• This may be explained by the fact that AMT would increase hepatic heme synthesis through the prolonged induction of delta-ALA synthetase, but it may not cause an increase in cytochrome P-450 heme because there are increases in the contents of cytochrome b5 and total heme [25].
• In the liver of rats exposed to trichloroethylene, cytochrome P-450 concentration and heme saturation of tryptophan pyrrolase (EC 1.13.11.11) are reduced; in addition, the activity of delta-aminolevulinate synthase (EC 2.3.1.37) increased [26].
• Rates of decline of the mRNAs encoding delta-aminolevulinate synthase (ALAs), cytochrome c oxidase subunit VIc (nuclear-encoded), and subunit III (mitochondrially encoded) in heart, liver, and muscle for 6 h following transcription inhibition with actinomycin D or ethidium bromide were measured [27].
• We investigated the effects of ethinyl estradiol (5 mg/kg body wt daily for 5 days, orally) and/or iron sorbitol (50 mg/kg body wt daily for 5 days, i.m.) on bile flow, bile salt independent fraction (BSIF), hepatic delta-aminolevulinate synthase (ALA-S) and uroporphyrinogen decarboxylase (URO-D) in female rats [28].

Analytical, diagnostic and therapeutic context of Alas1

• In this study, we examined expression of HO-1 as well as non-specific delta-aminolevulinate synthase (ALAS1), the rate-limiting enzyme in heme catabolism and biosynthesis, respectively, in a rat model of PH produced by subcutaneous injection of MCT (60 mg/kg) [1].
• These data indicate that hydrocortisone and adrenalectomy can significantly influence the extent of the induction of heme oxygenase produced by CoCl2, but that both the initial decline and the rebound induction of delta-aminolevulinate synthase associated with this metal treatment are apparently independent of these endocrine controls [7].
• Partial hepatectomy produced a significant depression in delta-ALA synthetase and delta-ALA dehydratase, and induction in haem oxygenase at an early stage of regeneration [29].

References