Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.61 (porphobilinogen deaminase)
 637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activities of the enzymes of heme biosynthesis (except protoporphyrin oxidase) have been followed during the induction of Friend cells in culture. All the enzyme activities increased after induction with dimethyl sulfoxide. The activities of the intermediate enzymes were much higher than those of delta-aminolevulinate synthase [succinyl-CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37], the initial enzyme, or ferrochelatase (protoheme ferro-lyase, EC 4.99.1.1), the final enzyme of the pathway. Ferrochelatase activity was not detectable in the uninduced cell. delta-Aminolevulinate synthase activity increased during the first 24 hr of induction; porphobilinogen deaminase activity began to increase after 48 hr and ferrochelatase activity, after 72 hr. However, the induction of heme synthesis followed the same time course as that of ferrochelatase activity, not that of delta-aminolevulinate synthase activity. The cellular growth medium was found to contain traces of protoporphyrins. Thus, ferrochelatase is shown to be rate limiting for heme synthesis during early stages of Friend cell induction. A Friend cell variant (Fw), which is not inducible except in the presence of exogenous hemin, was also studied. All the enzymes of heme synthesis except ferrochelatase were inducible by butyric acid. Ferrochelatase was not inducible by butyric acid or hemin plus butyric acid. These cells also excrete protoporphyrin, The failure to induce ferrochelatase activity is believed to be the cause of, not a consequence of, the noninducibility of this cell line.
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PMID:Heme biosynthesis in Friend erythroleukemia cells: control by ferrochelatase. 28 6

The present study was undertaken to explore the effect of the presence of hepatic tumors induced by diethylinitrosamine (DENA) on the metabolic heme pathway, and to assess whether these tumors can modify the response of rats to the porphyrinogenic drug hexachlorobenzene (HCB) and whether the above mentioned effects occur to a greater extent in females than males. The results obtained showed that: a) Females were more susceptible to the hepatocarcinogenicity of DENA than males. b) Female normal and DENA treated rats were more susceptible than male rats to the porphyrinogenicity of HCB. c) The presence of hepatic DENA induced tumors could diminish basal hepatic ferrochelatase activity. d) Hepatic tumors could modify the response of animals to a porphyrinogenic drug such as HCB. Thus, both female and male DENA/HBC rats accumulated more porphyrins and showed a lower delta-aminolevulinate synthase and uroporphyrinogen I synthase induction than HCB rats. e) The heme pathway was functional in DENA induced tumors in both male and female rats but they were little affected by HCB.
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PMID:Sex comparison of heme pathway in rats bearing hepatic tumors. 178 Oct 34

Changes in the level of transcripts encoding enzymes of the heme biosynthetic pathway as well as those encoding ubiquitous proteins were examined in murine Friend virus-transformed erythroleukemia cells during erythroid cell differentiation induced by chemicals including dimethyl sulfoxide (DMSO). Early changes following DMSO treatment were marked decreases in mRNAs for three ubiquitous proteins, i.e., a 70 kDa heat shock protein (less than 6 h), heme oxygenase and nonspecific delta-aminolevulinate synthase (ALAS) (less than 12 h). These changes were followed by sequential increases in mRNAs for enzymes in the heme biosynthetic pathway. Namely, mRNAs for the erythroid-specific ALAS, delta-aminolevulinate dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase started to increase at 12, 18, 18-24 and 24 h, respectively. Nuclear runoff studies revealed that these changes are largely transcriptional. Treatments with other inducers of erythroid differentiation, e.g., hexamethylene bisacetamide, n-butyric acid and N'-methylnicotinamide, also showed similar effects on mRNAs as those following DMSO. These findings suggest that both suppression of ubiquitous genes and activation of heme pathway enzyme genes are associated with erythroid differentiation, and the former occurs preceding changes in the latter.
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PMID:Sequential activation of genes for heme pathway enzymes during erythroid differentiation of mouse Friend virus-transformed erythroleukemia cells. 195 53

Carbamazepine, a drug which is widely used in neurological diseases, has a porphyrogenic effect in chick embryo liver cells in culture. It increased the concentration of cellular porphyrins by 80-fold and delta-aminolevulinate synthase activity by 4-fold. The increase in the accumulation of porphyrins preceded that of ALAS activity. Measurements of the activities of aminolevulinate dehydrase, porphobilinogen deaminase, and uroporphyrinogen decarboxylase showed that C inhibits UROD up to nearly 50% and PBGD activity up to 20%, but does not affect the activity of ALAD. The pattern of accumulation of porphyrins, mainly uro- and heptacarboxylporphyrin, is compatible with an inhibition of UROD. We may, therefore, conclude that the porphyrogenic effect of C in monolayers of chick embryo liver cells is the result of its inhibitory effect on the activity of UROD.
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PMID:The influence of carbamazepine on the heme biosynthetic pathway. 409 16

A new spectrofluorometric assay is described for quantitating uroporphyrinogen I synthase (EC 4.3.1.8) activity in volumes of human blood as small as 2 mul. By this sensitive assay the inheritance of the enzyme's activity has been studied and the genetic defect for acute intermittent porphyria has been confirmed to be autosomal dominant in nature. There is a 3-fold range of uroporphyrinogen I synthase activity in erythrocytes in the normal population, with a mean V(max) +/- SD of 35.7 +/- 8.4 nmol of uroporphyrinogen I formed per ml of erythrocytes per hr, at 37 degrees . One-half this level of enzyme activity (18.0 +/- 5.0) is found in erythrocytes from patients with clinically manifest acute intermittent porphyria; and in erythrocytes from those of their relatives, including prepubertal children, who have the latent gene defect for the disease. The K(m) of erythrocyte enzyme of normal people is 12.3 +/- 3.9 muM, whereas the K(m) of the erythrocyte enzyme of patients with acute intermittent porphyria is 6.2 +/- 3.9 muM, as determined on whole blood lysates. Three enzymic changes have now been identified in patients with acute intermittent porphyria; a high level of delta-aminolevulinate synthase activity; a low level of uroporphyrinogen I synthase activity; and a deficiency of steroid Delta(4)-5alpha reductase activity.
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PMID:A microassay for uroporphyrinogen I synthase, one of three abnormal enzyme activities in acute intermittent porphyria, and its application to the study of the genetics of this disease. 452 87

The mode of expression of delta-aminolevulinate synthase (ALAS), as well as that of mRNAs for other heme pathway enzymes, was examined in the rat Harderian gland. Northern blot and in situ hybridization analyses demonstrated that the non-specific ALAS (ALAS-N) mRNA is highly expressed in this tissue, whereas the erythroid-specific ALAS (ALAS-E) mRNA is not. Immunoblot analysis of ALAS also confirmed this finding at the protein level. ALAS-N mRNA was maximally induced in the Harderian gland and was not increased further by treatment of animals with 2-allyl-2-isopropylacetamide (AIA). The levels of mRNAs for other heme pathway enzymes, i.e., delta-aminolevulinate dehydratase, porphobilinogen deaminase, uroporphyrinogen decarboxylase, and coproporphyrinogen oxidase, also were increased markedly in the Harderian gland and not influenced by AIA treatment. The level of ferrochelatase (FeC) mRNA in the gland was, however, lower than that in the liver. The gland contained an extremely high level of protoporphyrin, while heme was undetectable. Microsomal heme oxygenase-1 (HO-1) mRNA levels were significantly higher in the Harderian gland than in the liver. When isolated glands were incubated with hemin in vitro in organ cultures, the level of HO-1 mRNA was increased, whereas the ALAS-N mRNA level was not. These findings indicate that markedly elevated levels of protoporphyrin and extremely low levels of heme in the Harderian gland are the results of both decreased expression of FeC and markedly increased expression of ALAS-N and HO-1. The constitutive expression of the ALAS-N gene in the Harderian gland suggests a novel transcriptional control mechanism of this gene.
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PMID:Novel regulation of delta-aminolevulinate synthase in the rat harderian gland. 911 83

Heme is not only a very important prosthetic group that modulates the structure and activity of heme proteins but also a regulatory molecule that controls metabolic pathways and the biosynthesis of various proteins. However, investigation into heme regulatory effects in higher vertebrates has been hampered by the lack of a suitable animal model. A knockout mouse with targeted disruption of porphobilinogen deaminase, the third enzyme of the heme pathway, has been generated in our laboratory and used in the present study as an in vivo model of heme deficiency to explore diverse heme regulatory properties. In this model with a defined heme disturbance, we observed a superinductive response of delta-aminolevulinate synthase, the first enzyme in heme synthesis, after phenobarbital treatment. We also found that limited heme is associated with decreased induction of cytochrome P450 by phenobarbital as a consequence of impaired gene transcription. This inhibitory effect is isoenzyme-specific, being significant for cyp2a5. The activity and mRNA level of this particular cytochrome P450 are significantly lower in the phenobarbital-induced porphobilinogen deaminase-deficient mice (55% and 43%, respectively), but its expression can be restored to normal values when exogenous heme is administered. Other heme proteins, namely neuronal nitric oxide synthase and soluble guanylate cyclase, function normally in mice with limited heme. Our results demonstrate that the expression of various heme proteins is differentially regulated in conditions of reduced heme availability. Moreover, our findings emphasize the importance of heme protein function in the genesis of pathophysiological manifestations in acute intermittent porphyria.
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PMID:Limited heme synthesis in porphobilinogen deaminase-deficient mice impairs transcriptional activation of specific cytochrome P450 genes by phenobarbital. 1110 24

The Syrian hamster Harderian gland (HG), representing a highly porphyrogenic organ, was used as a model system for studying physiologically occurring damage of biomolecules by porphyrins and their precursors, phenomena associated with from the pathological situation of porphyrias. The species used exhibits the peculiarity of much higher porphyrogenesis in females than in males, offering possibilities for comparison of effects by different porphyrin levels in one species. Since concentrations of free, and therefore, radical-generating porphyric metabolites are difficult to determine in the presence of high amounts of secreted and crystallizing porphyrins, which are, moreover, mainly surface-reactive, and since indications existed for temporal changes in the oxidative stress caused by these molecules, the following approach was chosen: in HGs of both females and males, activities of the relevant porphyric enzymes, delta-aminolevulinate synthase (ALA-S), delta-aminolevulinate dehydratase (ALA-D) and porphobilinogen deaminase (PBG-D), were determined throughout the circadian cycle. Results were compared with the temporal patterns of lipid peroxidation and protein damage in the same glands. In females, a strong correspondence was observed between protein carbonyl and lipid peroxidation, peaking at the end of both photophase and scotophase; maximal activities of the three porphyric enzymes ALA-S, ALA-D, and PBG-D either coincided or slightly preceded the peaks of oxidative damage. In males, lower enzyme activities, especially in PBG-D, were associated with weakly expressed rhythmicity. Correspondingly, lipid peroxidation was lower and exhibited a smaller rhythm amplitude; protein carbonyl of males showed a temporal pattern differing from that of females, with regard to amplitude and phasing. These data are in agreement with morphological observations demonstrating particularly severe cell damage in the female HG under normal conditions.
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PMID:Porphyric enzymes in hamster Harderian gland, a model of damage by porphyrins and their precursors. A chronobiological study on the role of sex differences. 1131 Dec 10

Zinc mesoporphyrin (ZnMP) is a potent inhibitor of heme oxygenase (HO) and represses 5-aminolevulinic acid synthase (ALAS). These properties make it a potential candidate for treatment of inducible acute hepatic porphyrias, diseases characterized by neurovisceral symptoms, and massive ALAS induction. Effects of intraperitoneal ZnMP (2.5-10 micromol/kg/d) and heme arginate (3-6 mg/kg/d) on plasma levels of 5-aminolevulinic acid (ALA), on messenger RNA (mRNA), and activity of hepatic ALAS and HO were studied in porphobilinogen deaminase-deficient mice treated with phenobarbital (100 mg/kg/d) to induce ALAS. ZnMP (5 micromol/kg/d) led to a significant reduction of plasma ALA levels to 31% of controls (P < .01) by lowering the activity of hepatic mitochondrial and cytosolic ALAS to 29% and 25% of controls, respectively (P < .03). ZnMP decreased the mRNA levels of hepatic ALAS to 53% (P < .03) of controls and this repression was more pronounced than that achieved with heme arginate. In contrast to heme arginate, ZnMP led to a significant reduction of HO activity. We conclude that the combined effect of ZnMP on highly induced ALAS and on HO may be of potential benefit for human acute hepatic porphyrias and therefore merits further in vivo investigations addressing questions raised by this study.
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PMID:Zinc mesoporphyrin represses induced hepatic 5-aminolevulinic acid synthase and reduces heme oxygenase activity in a mouse model of acute hepatic porphyria. 1134 51

Effects of the prooxidant delta-aminolevulinic acid (ALA) and the antioxidant melatonin (MEL) were investigated in the male Syrian hamster Harderian gland (HG). Rodent Harderian glands are highly porphyrogenic organs, which may be used as model systems for studying damage by delta-aminolevulinic acid and its metabolites, as occurring in porphyrias. Chronic administration of delta-aminolevulinic acid (2 weeks) markedly decreased activities of the porphyrogenic enzymes delta-aminolevulinate synthase (ALA-S) and delta-aminolevulinate dehydratase (ALA-D) and of the antioxidant enzymes superoxide dismutase (SOD), glutathione reductase (GR) and catalase (CAT), whereas porphobilinogen deaminase (PBG-D) remained unaffected. This treatment led to increased lipid peroxidation (LPO) and oxidatively modified protein (protein carbonyl) as well as to morphologically apparent tissue damage. Melatonin also caused decreases in delta-aminolevulinate synthase, delta-aminolevulinate dehydratase, superoxide dismutase, glutathione reductase and catalase. Despite lower activities of antioxidant enzymes, lipid peroxidation and protein carbonyl were markedly diminished. The combination of delta-aminolevulinic acid and melatonin led to approximately normal levels of delta-aminolevulinate dehydratase, glutathione reductase, catalase and protein carbonyl, and to rises in superoxide dismutase and porphobilinogen deaminase activities; lipid peroxidation remained even lower than in controls and the appearance of the tissue revealed a protective influence of melatonin. These results suggest that melatonin may have profound effects on the oxidant status of the Harderian gland.
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PMID:Melatonin protects against delta-aminolevulinic acid-induced oxidative damage in male Syrian hamster Harderian glands. 1190 25


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