Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Promastigotes of Leishmania donovani (Dd-8 strain) showed presence of important key enzymes of heme synthesizing (delta-aminolevulinic acid synthase and ferrochelatase) and degrading (heme oxygenase and biliverdin reductase) systems, classical leishmanicidal drugs viz allopurinol, amphotericin B, pentamidine and CDRI compound 93/202 inhibited the heme oxygenase activity of the parasite, whereas, delta-aminolevulinic acid synthase activity practically remained unaffected. The Km, Vmax and pH values of heme oxygenase of promastigotes were found to be 1666 microM hemin, 625 nmol of bilirubin formed h-1 mg protein-1 and 7.5 respectively. The findings suggest the presence and importance of heme metabolism in the de novo synthesis of different hemoproteins of the Leishmania parasite as well as the detoxification and its defence against biological insults.
Mol Cell Biochem 1997 Jun
PMID:Heme metabolism in promastigotes of Leishmania donovani. 920 97

Disulfiram (Antabuse) (DSF) has been reported to protect rats and other animals from the effects of hyperbaric hyperoxia at 4 to 6 ATA (atmospheres). In contrast, DSF and diethyldithiocarbamate (DDC), its metabolite, accelerate the toxic effects in rats of 100% oxygen at 1 to 2 ATA. We have examined the effects of DSF and DDC on glutathione (GSH) levels in bovine pulmonary artery endothelial cells and Chinese hamster ovary cells. Increases in intracellular GSH occurred 8 to 24 h after addition of DSF to the culture media. These increases in intracellular GSH were associated with increases in the rate of uptake of cystine into the cells. DDC was a less effective inducer of cystine uptake and increased intracellular GSH levels than was DSF. At the concentrations used, neither DDC nor DSF caused significant decreases in intracellular superoxide dismutase levels. Exogenous sulfhydryl compounds including GSH and cysteine partially blocked the induction of cystine transport by DSF or DDC, suggesting that the induction might be mediated through a sulfhydryl reaction between DSF and some cellular components. The increases in GSH in the cultured cells were not significant by 4 h of exposure. In contrast, other stress proteins including heme oxygenase are induced by 2 to 4 h after DSF addition. In previously reported in vivo studies, DSF treatment protected against hyperbaric oxygen damage after as little as 1 to 4 h pre-exposure. This suggests that effects of DSF exposure other than GSH augmentation may be responsible for the protective effects seen in vivo.
Am J Respir Cell Mol Biol 1997 Aug
PMID:Induction of cystine transport and other stress proteins by disulfiram: effects on glutathione levels in cultured cells. 927 11

Toxicosis syndrome of fasting pregnant ewes has a close similarity to human preeclampsia (hypertension, albuminuria). The common etiological factor might be oxidative hemolysis and heme-induced endothelial damage. Ewes (5 starving, 5 control) at 130-135 gestational days with a 96-h fasting period followed by refeeding were used. Blood pressure, platelet count, electrolytes, kidney and liver function parameters, as well as plasma glucose, hemoglobin/heme, free thiol groups and Trolox equivalent antioxidant capacity, and plasma iron and ferritin levels were measured. Statistical significance was assessed using Student's t test (P < 0.05). Besides hypertension and renal disturbances, hemolysis, elevated liver enzymes and low platelet count, characteristic of human HELLP syndrome, were also present. In the first 24 h of glucose deprivation there was a significant rise in both the plasma hemoglobin/heme and indirect bilirubin concentrations. The antioxidant free thiol levels decreased significantly the next day, without any change in the total antioxidant capacity of the plasma. While the loss of calcium and magnesium levels related to the similarity to preeclampsia, reduced plasma iron concentrations referred to species differences in iron homeostasis. An oxidative stress causing hemolysis in a glucose-6-phosphate dehydrogenase-deficient animal model was proven by the loss of free thiols after glucose deprivation. The activation of the oxidative stress protein heme oxygenase was a signal of endothelial cell injury, the primary cause of pregnancy-induced hypertension.
Biochem Mol Med 1997 Oct
PMID:The pathogenetic role of heme in pregnancy-induced hypertension-like disease in ewes. 936 99

Heme metabolism normally involves enzymatic conversion to biliverdin and subsequently to bilirubin, catalyzed by heme oxygenase and biliverdin reductase, respectively. We examined the ability of exogenously added hemin, biliverdin, or bilirubin to regulate Cyp1a1, an enzyme that may be active in bilirubin elimination. A substantial dose-dependent increase in Cyp1a1 mRNA occurred after treatment of Hepa 1c1c7 cells with either of the three compounds. This increase was readily apparent 1 hr after treatment with biliverdin or bilirubin but required >/=2 hr with hemin. Treatment of Hepa 1c1c7 cells with these compounds also caused a dose-dependent increase in Cyp1a1-dependent 7-ethoxyresorufin-O-deethylase (EROD) activity. Of the three compounds, bilirubin produced the greatest maximal increase in Cyp1a1 mRNA and EROD (5.5-, 10.5-, and 15-fold for 100 microM hemin, biliverdin, and bilirubin, respectively) activity. The RNA polymerase inhibitor actinomycin D completely blocked Cyp1a1 induction by these compounds, indicating a requirement for de novo RNA synthesis via transcriptional activation. The protein synthesis inhibitor cycloheximide did not affect Cyp1a1 mRNA induction, indicating a lack of requirement for labile protein factors. In contrast, EROD induction by hemin, biliverdin, or bilirubin was completely blocked by cycloheximide treatment, indicating that the increase in enzyme activity is dependent on increased Cyp1a1 apoprotein synthesis. Aryl hydrocarbon receptor (AHR)- and AHR nuclear translocator-deficient mutant Hepa 1c1c7 cells did not exhibit increased Cyp1a1 mRNA or EROD activity after treatment with these compounds, indicating the requirement for a functional AHR for this response. Consistent with this, hemin, biliverdin, and bilirubin were able to induce expression of the dioxin-response element/luciferase reporter plasmid pGudLuc1.1 after transient transfection into wild-type Hepa 1c1c7 cells. Gel retardation assays demonstrated that bilirubin, but not hemin or biliverdin, was able to transform the AHR to a form capable of specifically binding to a 32P-labeled oligonucleotide containing a dioxin-response element sequence. These data indicate that bilirubin induces Cyp1a1 gene transcription through direct interaction with the AHR. In contrast, hemin and biliverdin seem to induce Cyp1a1 indirectly by serving as precursors to the endogenous formation of bilirubin via normal heme metabolism pathways. This is the first direct demonstration that the endogenous heme metabolite bilirubin can directly regulate Cyp1a1 gene expression and enzymatic activity in an AHR-dependent manner.
Mol Pharmacol 1997 Oct
PMID:Aryl hydrocarbon receptor-dependent induction of cyp1a1 by bilirubin in mouse hepatoma hepa 1c1c7 cells. 938 21

In cultured endothelial cells, incubation with TNF-alpha (50 ng/ml) for 72 h markedly reduced viability of endothelial cells. A 6-h pre-incubation with the nitric oxide (NO) donor linsidomine (SIN-1, 10-150 microM) protected endothelial cells in a concentration-dependent manner and increased viability by up to 59% of control. The unmetabolized parent compound molsidomine and the NO-free metabolite of SIN-1 3-morpholinoiminoacetonitrile (SIN-1C) were without cytoprotective effect. Cytoprotection by SIN-1 was completely abolished by the NO scavenger 2-phenyl-4,4,5,5, -tetramethylimidazoline-1-oxyl-3-oxide (PTIO, 30 microM). A cytoprotective effect comparable to SIN-1 was observed when preincubating the cells with dibutyryl cyclic GMP (10-100 microM). Moreover, no protection by SIN-1 occurred in the presence of cycloheximide (1 microM) or 1H--1,2,4-oxadiazole-4, 3-a-quinoxalin-1-one (ODQ, 0.1 microM), a selective inhibitor of soluble guanylyl cyclase. Tin protoporphyrin-IX (SnPP, 25 microM), an inhibitor of heme oxygenase, was found to attenuate SIN-1-induced cytoprotection. Our results demonstrate that SIN-1 produces a long-term endothelial protection against cellular injury by TNF-alpha, presumably via a cyclic GMP-dependent pathway leading to up-regulation of protective proteins such as heme oxygenase.
J Mol Cell Cardiol 1997 Dec
PMID:The nitric oxide donor SIN-1 protects endothelial cells from tumor necrosis factor-alpha-mediated cytotoxicity: possible role for cyclic GMP and heme oxygenase. 944 36

Carbon monoxide (CO), an activator of soluble guanylate cyclase and generated enzymatically by heme oxygenase-2 (HO-2), is thought to function as an intra- and intercellular neurotransmitter in the central and peripheral nervous system. In the present study, the distribution of HO-2 in airway nerves from both humans and guinea pigs was assessed. HO-2 was found in all neuronal perikarya of the intrinsic ganglia of guinea-pig airways and in all ganglion nerve cell bodies localized to the trachea and bronchi of humans. By contrast, nerve fibers innervating the smooth muscle, lamina propria, and epithelium of the airways in both species were devoid of HO-2 immunoreactivity. HO-1, the inducible isoform of heme oxygenase, was not found in airway nerves. The pattern of distribution of HO-2 observed suggests that CO might serve as a modulator of synaptic neurotransmission in the lung and airways rather than as a bona fide neurotransmitter in the smooth muscle, vasculature, or glands. Consistent with this hypothesis, 8-bromo-cyclic guanosine monophosphate (cGMP) (30 microM), a stable, pharmacologically active analog of cGMP, markedly inhibited vagally-mediated cholinergic contractions of the isolated guinea-pig trachea. In subsequent studies, however, neither inhibiting heme oxygenase with zinc protoporphyrin-IX (30 microM) nor inhibiting the soluble isoform of guanylate cyclase with ODQ (3 microM) had measurable effects on vagally-mediated cholinergic contractions of the trachea. These results indicate that CO could play a modulatory role in efferent (parasympathetic) synaptic neurotransmission in the airways, but under normal conditions may not be activated to an appreciable extent during periods of elevated vagal activity.
Am J Respir Cell Mol Biol 1998 Feb
PMID:Localization of heme oxygenase-2 immunoreactivity to parasympathetic ganglia of human and guinea-pig airways. 947 16

To determine if overexpression of the human heme oxygenase (HO-1) protects retinal pigment (RPE) cells from hemoglobin toxicity, a human RPE cell line was infected by an adenoviral vector containing the HO-1 (Ad-HO-1) gene or transfected with a plasmid containing the cytomegalovirus promoter and HO-1 cDNA (pRc/CMV-HO-1) complexed to cationic liposomes. Phase contrast microscopy and acid phosphatase activity were examined to insure homogeneity of the cell line. Mitochondrial cytochrome and microsomal heme content were measured in both transduced and control cells. RPE cells were then challenged with hemoglobin and their viability estimated. We determined that cells transfected with Ad HO-1 overexpressed HO-1 compared to control cells: HO-1 mRNA levels were increased 3-fold within 3 days, decreasing in 7 days. In addition, we permanently transfected RPE cells with HO-1 gene. Transfected cell clones selected for neomycin resistance had elevated levels of HO activity 3-fold higher than control. Transfected cells exposed to hemoglobin had a survival rate of 93%; non-transfected cells had a 65-75% rate of survival. Transfected cells overexpressing HO-1 proved highly viable when challenged with hemoglobin. HO-1 appears to be an important component of the cellular anti-oxidant defense mechanisms against hemoglobin toxicity. However, the choice of transient or permanent expression of HO-1 against hemoglobin toxicity and hemorrhage needs to be further evaluated.
Int J Mol Med 1998 Apr
PMID:Retinal pigment epithelial cell-based gene therapy against hemoglobin toxicity. 985 79

Carbon monoxide (CO) is an endogenously generated gas that may play an important physiological role in the circulation. CO is generated by vascular cells as a byproduct of heme catabolism, in which heme oxygenase (HO) catalyzes the degradation of heme to biliverdin, iron and CO. Two distinct isoforms of HO have been identified in vascular tissue. The HO-2 isoform is constitutively expressed and likely mediates the release of CO under normal physiologic conditions. In contrast, the HO-1 isoform is strongly induced in vascular cells by various stress-associated agents and markedly increases CO synthesis during pathological conditions. The release of CO by vascular cells exerts both paracrine and autocrine effects on vascular smooth muscle cells (SMC) and circulating blood cells. CO regulates blood flow and blood fluidity by inhibiting vasomotor tone, SMC proliferation, and platelet aggregation. These vascular effects of CO are mediated via the activation of soluble guanylate cyclase and the consequent rise in intracellular guanosine 3',5'-cyclic monophosphate levels in target tissues. CO may also play a role in various cardiovascular disorders, including endotoxin shock, ischemia-reperfusion, hypertension, and subarachnoid hemorrhage. This review will focus on the recent progress made in understanding the regulation and function of CO in the vasculature.
Int J Mol Med 1998 Sep
PMID:Carbon monoxide and vascular cell function (review). 985 96

The endothelium of the lung is sensitive to the toxic effects of oxygen, and early evidence of toxicity is characterized by protein leak and extravasation of red blood cells. The overproduction of oxygen free radicals plays a critical role in the pathophysiology of a hyperoxic lung injury. Recently, heme oxygenase 1 (HO-1), the rate-limiting enzyme in the metabolism of heme, has been found to have a protective role in oxidant injury. Our laboratory and others have identified HO-1 as a hyperoxia-inducible protein. In this study, we characterized HO-1 expression and evaluated its regulation in human pulmonary endothelial cells. Hyperoxia results in a relatively small increase in HO-1 expression; however, this induction is potentiated by heme and dramatically potentiated in the presence of free iron. This is probably more reflective of the in vivo situation in which there is extravasation of heme and iron products. We also found that HO-1 expression depended on chelatable iron. The iron chelator desferrioxamine not only inhibited the iron- dependent potentiation of HO-1 in response to hyperoxia but also inhibited both hyperoxia and basal expression. On the basis of inhibitor studies and nuclear run-on assays, we demonstrated that this induction is transcriptionally dependent. We also evaluated 4.5 kb of the human HO-1 promoter region and demonstrated that this region has promoter activity to the stimulus heme; however, there was no evidence of promoter activity to either iron or hyperoxia. This diversity of promoter activity to heme, heavy metals, and hyperoxia is unique to the human HO-1 gene.
Am J Respir Cell Mol Biol 1999 Apr
PMID:Iron regulates hyperoxia-dependent human heme oxygenase 1 gene expression in pulmonary endothelial cells. 1010 Oct 13

Human monocytes avidly ingest malarial pigment, hemozoin. Phagocytosed hemozoin persists in the monocyte for a long time and modifies important monocyte functions. Stability of phagocytosed hemozoin may depend on modifications of the hemozoin heme moiety or reduced ability to express heme-inducible heme oxygenase. We show here that the spectral characteristics of alkali-solubilized hemozoin were identical to those of authentic heme, although hemozoin was solubilized by alkali much more slowly than authentic heme. Alkali-solubilized hemozoin was a substrate of microsomal rat heme oxygenase and bilirubin reductase, with bilirubin as the main final product. Hemozoin feeding to human monocytes did not induce heme oxygenase, but authentic heme and alkali-solubilized hemozoin supplemented to hemozoin-fed monocytes induced heme oxygenase and were degraded normally. Lysosomes isolated from hemozoin-fed monocytes released only traces of heme while lysosomes from erythrocyte-fed monocytes liberated considerable quantities of heme. Lack of heme release from hemozoin did not depend on proteolysis-resistant, heme-binding proteins, since lysosomal proteases fully degraded hemozoin-associated proteins but did not solubilize hemozoin. In conclusion, our data indicate that lack of induction of HO1 is due to the intrinsic structural characteristics of hemozoin and not to hemozoin-mediated impairment of the mechanism of HO1 induction.
Mol Biochem Parasitol 1999 May 15
PMID:Hemozoin stability and dormant induction of heme oxygenase in hemozoin-fed human monocytes. 1037 94


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>