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PubMed1996

Generation of reactive oxygen species by Co(II) from H2O2 in the presence of chelators in relation to DNA damage and 2'-deoxyguanosine hydroxylation.

The generation of reactive oxygen species by Co(II) from H2O2 in the presence of chelators and related DNA damage was investigated by electron spin resonance (ESR), electrophoretic assays, and high-performance liquid chromatography (HPLC). Incubation of Co(II) with beta-alanyl-3-methyl-L-histidine (anserine) and H2O2 generated .OH radicals. Omission of any one component sharply reduced the amount of .OH radicals generated, indicating that anserine modulated the oxidation potential of Co(II) to enhance its capability to generate .OH radicals from H2O2. Formate only moderately decreased the .OH radical generation, while ethanol had no observable effect, indicating that the generation of .OH radical is site specific. The metal ion chelator 1,10-phenanthroline reduced the .OH radical generation, and deferoxamine suppressed it with the formation of deferoxamine nitroxide radical. Electrophoretic assays using both lambda Hind III linear DNA and PM2 supercoiled DNA showed that .OH radicals generated from a mixture of Co(II), H2O2, and anserine caused DNA strand breaks. A mixture of Co(II), H2O2, and 1,10-phenanthroline also caused DNA strand breaks, which were inhibited by sodium azide, indicating that 1O2 was involved in DNA damage. HPLC measurements showed that .OH radicals and 1O2 generated by Co(II) reactions caused 2'-deoxyguanosine hydroxylation to form 8-hydroxy-2'-deoxyguanosine. ESR spin trapping measurements provided evidence for 1O2 generation by Co(II) from H2O2 in the presence of 1,10-phenanthroline. The results indicate that the oxidation potential of Co(II) can be modulated by chelators to facilitate its generation of reactive oxygen species from H2O2. These species may be involved in Co(II)-induced cellular damage.

Anserine↗
PubMed2002

Iron enhancement of oxidative DNA damage and neuronal cell death induced by salsolinol.

A group of naturally occurring isoquinoline alkaloids have been detected in certain regions of mammalian brain. One such compound is salsolinol (SAL; 1-methyl-6, 7-dihydroxy-1,2,3,4-tetrahydroisoquinoline). This endogenous isoquinoline derivative has been considered to be implicated in the pathophysiology of chronic alcoholism and Parkinsonism. The present study deals with the DNA strand scission induced by SAL in the presence of iron. Incubation of phiX174 DNA with SAL and ferric ion led to conversion of the supercoiled DNA to open circular and linear forms, which was inhibited by the iron chelator deferoxamine, catalase, and scavengers of reactive oxygen species. SAL in combination with Fe(III) also produced 8-hydroxydeoxyguanosine in calf thymus DNA. Exposure of PC12 cells to SAL produced concentration-dependent reduction in viability, which was exacerbated by iron and ameliorated by deferoxamine.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2004

Iron bezoar retained in colon despite 3 days of whole bowel irrigation.

Concretion formation is a documented complication of large iron ingestions. The generally accepted treatment is supportive care, whole bowel irrigation, and intravenous deferoxamine for systemic toxicity. Laparotomy and gastrotomy have also been used in patients with a high iron burden and bezoar formation. Though experiments suggest that iron is poorly absorbed in the colon, there are no case reports of iron overdose without systemic toxicity, despite a retained colonic bezoar. We report the case of a 16-month-old who presented to an Emergency Department 19 h after an iron ingestion. Initial laboratory studies revealed an anion gap of 14 mEq/L, and a 20 h serum iron concentration of 429 mcg/dL. An abdominal radiograph revealed multiple pills throughout the stomach and small bowel; whole bowel irrigation was initiated. Deferoxamine was administered at 10 mg/kg/h and then stopped when the serum iron level reached 27 mcg/dL, 36 h later. At this time, the abdominal radiograph showed an iron bezoar remaining in the ascending colon despite a clear rectal effluent from whole bowel irrigation. Despite whole bowel irrigation over the next 36 h, the iron bezoar was not removed and actually migrated proximally in the colon. Treatment was stopped on the third day and a normal diet was instituted with prompt passage of the bezoar.

Antidotes↗
PubMed2002

Oxidative stress reproduces placental abnormalities of preeclampsia.

OBJECTIVE: The activities of placental superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), but not catalase, are lower than normal in preeclampsia, which could contribute to the uncontrolled placental production of lipid peroxides and thromboxane (TX). Oxidative stress, hyperlipidemia and increased iron levels in the maternal compartment in preeclampsia could be responsible for these placental changes by causing oxidative stress in the placenta. METHODS: We tested this possibility in vitro by exposing a trophoblast-like cell line, ED27, to a combination of linoleic acid (LA, 90 microM) and an oxidizing solution composed of hypoxanthine, xanthine oxidase and ferrous sulfate (OxLA) for 6 days. For these studies, the cells were treated with dexamethasone (10-8 M) for the first 72 hr. This was done to differentiate the cells into a phenotype more like syncytiotrophoblast cells as evidenced by production of beta-human chorionic gonadotropin (beta-hCG). RESULTS: After 6 days of exposure to OxLA, the activities of SOD and GSH-Px were significantly decreased as compared to exposure to LA alone. In contrast, catalase activity was increased by OxLA. The OxLA-induced decreases in SOD and GSH-Px activities were attenuated by deferoxamine, an iron chelator, suggesting a role for Fe2+ in the decreased activities. Compared to LA, OxLA significantly increased TX secretion and lipid peroxidation in cells and media at 2, 4 and 6 days. Deferoxamine inhibited the OxLA-induced increase in lipid peroxidation, but not the increase in TX. Isolation of trophoblast cells and villous core tissue from term placentas verified that antioxidant enzyme activity was localized primarily to the trophoblast cell compartment lending validity to the in vitro findings. CONCLUSIONS: These data mimic the changes in placental SOD, GSH-Px, catalase, TX and lipid peroxidation that occur in preeclampsia suggesting that maternal hyperlipidemia and increased iron levels may be responsible for placental oxidative stress and abnormalities in antioxidants and thromboxane.

Adult↗
PubMed1998

Infection due to Yersinia enterocolitica in a series of patients with beta-thalassemia: incidence and predisposing factors.

Over 15 years, 14 patients with yersiniosis in two North American comprehensive thalassemia clinics (0.6 cases per 100 patient-years) presented with fever (100%), diarrhea (86%), right-lower-quadrant abdominal pain (71%), bacteremia (57%), a palpable abdominal mass (36%), and pharyngitis (28%). Clinically apparent infection occurred within 10 days of blood transfusion in 57% of patients. Nine patients (64%) had only a modest elevation in serum level of ferritin (< 2,000 micrograms/L). Patients with focal abdominal findings had a higher body iron burden, as estimated by the serum ferritin level, and significant intraabdominal suppurative complications. Two patients were not receiving iron-chelating therapy with deferoxamine; one patient was receiving the experimental chelator deferiprone (L1). Iron-loaded patients with beta-thalassemia are at greatly increased risk for severe yersiniosis, even when their body iron burden (as indicated by the serum ferritin level) is only moderately elevated and they are not receiving iron-chelating therapy with deferoxamine.

Adolescent↗
PubMed1997

Iron overload alters innate and T helper cell responses to Candida albicans in mice.

The effect of iron overload on susceptibility of mice to Candida albicans infection and on the type of T helper (Th) immunity elicited was investigated. Iron overload greatly increased susceptibility to disseminated infection with low-virulence C. albicans cells of exogenous origin. The candidacidal activity and the ability to release nitric oxide and bioactive interleukin (IL)-12 were greatly impaired in neutrophils and macrophages from infected mice. CD4 T cells from spleens of iron-overloaded mice were found to produce high levels of IL-4 and IL-10 and low levels of interferon-gamma. Treatment of iron-overloaded mice with the iron chelator, deferoxamine, resulted in the cure of mice from infection, restored the antifungal effector and immunomodulatory functions of the phagocytic cells, and allowed the occurrence of CD4 Th1 protective antifungal responses. These data indicate that iron overload may negatively affect CD4 Th1 development in mice with candidiasis, a function efficiently restored by therapy with deferoxamine.

Animals↗
PubMed2000

Astrocytes generate isoprostanes in response to trauma or oxygen radicals.

Previous studies have shown that oxygen radical scavengers prevent the reduced cerebral blood flow that occurs following experimental traumatic brain injury. The exact chemical species responsible for the posttraumatic reduction in flow is unknown. We tested whether isoprostanes, which are formed by non-cyclooxygenase-dependent free radical attack of arachidonic acid and are vasoconstrictors of the cerebral circulation, are increased in astrocytes following stretch-induced trauma or injury with a free radical generating system. Isoprostane (8-epi-prostaglandin F2alpha) was analyzed in cells and in media by immunoassay. Confluent rat cortical astrocytes in culture were injured by a hydroxyl radical generating system consisting of hydrogen peroxide and ferrous sulfate or by rapid stretch of astrocytes grown on a deformable silastic membrane. Some cells were treated with the iron chelator deferoxamine for 1 h before injury. The hydroxyl generating system caused free and cell-bound isoprostanes to increase to more than 400% of control. After trauma, free and membrane bound isoprostanes increased to 321 +/- 34% and 229 +/- 23% of control, respectively, and posttraumatic increases were prevented by deferoxamine. Since astrocytes are in close proximity to cerebral vessels, posttraumatic free radical formation may increase the formation of isoprostanes, which in turn produce vasoconstriction and decrease cerebral blood flow.

Animals↗
PubMed1995

Novel 21-aminosteroidlike compounds prevent iron-induced free radical-mediated injury to vascular endothelial cells.

Free radicals appear to play a major role in the reperfusion injury of the myocardium. Iron chelators and antioxidants can prevent the reperfusion injury. The cellular source of free radicals during reperfusion is not clearly established. However, an important source may be the endothelial cells (EC). The protective effect of iron chelators and antioxidants on reperfusion injury of the myocardium may be partially mediated by their effect on vascular EC, which may attenuate the formation of hydroxyl radicals. We examined the protective effect of deferoxamine and antioxidants on iron-dependent free radical-mediated damage to EC and membrane lipid peroxidation and compared it with those of a new class of compounds (21-aminosteroids: U-74389F, U-74500A, U-78517F) which have both antioxidant and iron chelating properties. We examined viability of the EC and membrane lipid peroxidation using primary aortic EC. First, the effect of increasing iron concentration (0-3.8 microM) (added as ferric ammonium citrate) was characterized. We then examined the effect of deferoxamine (1-10 microM), butylated hydroxytoluene (BHT 1-10 mM), probucol (0.5-5.0 mM), allopurinol (1-1,000 microM), U-74389F (2-20 microM), U-74500A (1-5 microM), and U-78517F (0.1-1.0 microM) on reversing the effect of iron. With increasing iron concentration, there was a significant decrease in the viability of dog aortic or bovine pulmonary arterial EC as compared with NIH 3T3 or human fibroblasts. Equally, there was also a significant increase in lipid peroxidation of the cellular membranes. There were significant differences between the compounds with respect to their ability to maintain the viability of EC and prevent membrane lipid peroxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Allopurinol↗
PubMed1990

Hemorrhagic shock-induced bacterial translocation: the role of neutrophils and hydroxyl radicals.

We previously documented a relationship between xanthine oxidase activation, intestinal injury, and bacterial translocation (BT) in rats subjected to hemorrhagic shock. The current experiments were performed to determine the relative roles of hydroxyl radicals and neutrophils in the pathogenesis of shock-induced mucosal injury and BT. The incidence of BT was higher in the shocked rats (30 mm Hg for 30 min) than the sham-shock controls (87% vs 12.5%; p less than 0.01). Administration of the hydroxyl radical scavenger, dimethyl sulfoxide (DMSO), or the iron chelator, deferoxamine, reduced the incidence of BT from 87% to 20% and 40%, respectively (p less than 0.05). DMSO and deferoxamine appear to prevent shock-induced BT by blunting the magnitude of shock-induced mucosal injury. In contrast, neutrophil depletion did not prevent BT or protect the intestinal mucosa in shocked rats. Instead, the incidence of systemic spread of translocating bacteria past the mesenteric lymph nodes to the livers and spleens of the shocked rats was higher in the neutrophil-depleted rats (56%) than in any other group (p less than 0.01). Thus, shock-induced BT and intestinal injury appear to be mediated by oxidants (.OH) derived from xanthine oxidase, rather than granulocytes.

Animals↗
PubMed1998

Reactive oxygen species in reoxygenation injury of rat brain capillary endothelial cells.

OBJECTIVE: To clarify the mechanism of anoxia/reoxygenation (A/R) injury of rat brain capillary endothelial cells (BCEC). METHODS: BCEC isolated from Sprague-Dawley rats by enzymatic treatment and centrifugation were subjected to anoxia (95% N2, 5% CO2) for 20 minutes and then to reoxygenation (95% air, 5% CO2) for 3 hours. Enzyme inhibitors, including oxypurinol, indomethacin, and N(G)-nitro-L-arginine methyl ester, or specific free-radical scavengers, such as superoxide dismutase, catalase, and the ferric iron chelator deferoxamine, were added before A/R injury. The BCEC were incubated in a range of Ca2+ concentrations from 1 to 0.01 mmol/L during A/R injury. Cytotoxicity was assayed by release of intracellular lactate dehydrogenase (LDH). RESULTS: With A/R injury, LDH release from the control group (no protective agents) significantly increased (44.8 +/- 3.3%), compared with a small increase in a normoxic group. BCEC treated with oxypurinol, indomethacin, or N(G)-nitro-L-arginine methyl ester showed suppression of LDH release. LDH release was almost totally suppressed by superoxide dismutase and partially by catalase or deferoxamine. The LDH release was partly dependent on calcium concentration. CONCLUSION: BCEC subjected to A/R become potent generators of free radicals, especially superoxide anion. Free radical production depends on both xanthine oxidase and cyclooxygenase pathways. Peroxynitrite and extracellular Ca2+ both contribute importantly to reoxygenation injury of BCEC.

Animals↗
PubMed1996

Protection of isolated lung from reperfusion injuries by rinsing with high colloidal osmotic solution with deferoaxmine.

We examined the efficacy of rinsing isolated lungs subjected to prolonged hypothermic storage with a high colloidal osmotic pressure solution prior to ex vivo blood reperfusion in order to preserve physiologic functions, suppress peroxidation of mitochondrial membranes, and inhibit infiltration of neutrophils. Isolated rabbit lungs were flushed with a Rinse-1 solution (289 mOsm/kg H2O) to remove remaining blood and immersed in physiologic saline at 8 degrees C for 24 hr. The control group received blood reperfusion immediately after storage; the Rinse-1 group was rinsed with Rinse-1 solution before blood reperfusion and the Rinse-2 group with Rinse-2 solution (312 mOsm/kg H20) including deferoxamine. Reperfused blood was passed through an artificial membranous lung to reduce oxygen tension (PO2) to the venous level, and time-dependent changes in airway pressure (AWP), pulmonary artery pressure (PAP), and PO2, as a measure of gas-exchange capability were examined. We estimated the lipid peroxide level in mitochondrial membranes as thiobarbituric acid-reactive substances (TBARS), i.e., malonedialdehyde, and neutrophil infiltration into lung tissue by measuring myeloperoxidase activity after 60 min of blood reperfusion. The PO2 was significantly higher in both rinsed groups compared with the control, while neither AWP nor PAP was significantly different in the three treatment groups. Both mitochondrial TBARS and myeloperoxidase activity were significantly higher in the control group compared with either rinsed group. These results indicate that rinsing stored lungs with a solution of high colloidal osmotic pressure prior to blood reperfusion was effective in preserving physiologic function and inhibiting neutrophil infiltration. Addition of deferoxamine was markedly effective in reducing TBARS formation and lessening reperfusion injury of stored lungs.

Animals↗
PubMed1994

Effects of stroma-free hemoglobin solutions on pulmonary vascular resistance and mediator release in the isolated perfused rabbit lung.

The aim of this study was to evaluate the effect of an ultrapure bovine stroma-free hemoglobin (SFH) on pulmonary vascular resistance and mediator release and to analyze potential mechanisms of action in the isolated perfused rabbit lung model. Repetitive bolus applications of small amounts of bovine SFH were examined which resulted in a reproducible acute increase of pulmonary vascular resistance of approx. 9 mmHg (controls, n = 6). It was tested whether the platelet-activating factor (PAF) antagonist WEB 2086 (50 microM; n = 6), the cyclooxygenase blocker diclofenac (10 micrograms/ml; n = 6), the iron-chelating agent deferoxamine (500 micrograms/ml, n = 6) and the radical scavenger catalase (5000 U/ml; n = 6) exert a protective effect on vasoconstrictor response to SFH. The pressure increase was completely suppressed in the lungs pretreated with WEB 2086, whereas diclofenac, deferoxamine and catalase failed to inhibit the vasoconstriction due to SFH. No significant differences in either TXB2 generation or in histamine release were found in the WEB 2086 group compared with untreated lungs. The results point towards the crucial role of PAF in mediation of vasoconstrictor side effects due to SFH.

Animals↗
PubMed1994

Complement activation by the hydroxyl radical during intestinal reperfusion.

This study examines the hypothesis that hydroxyl radical (OH.) generation during intestinal reperfusion activates the complement system forming the potent chemotaxin C5a. Anesthetized Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IIR). Complement (C) activation was assessed by measuring total plasma C activity and C5a-related chemotaxis and leukoaggregation. Dimethylthiourea and the iron chelator deferoxamine were utilized to assess the role of the OH. in the activation of C in this model. Sham-operated animals served as controls. Total plasma C activity of animals sustaining IIR was 64% of controls (p < .05). Plasma of animals sustaining IIR induced greater chemotaxis and leukoaggregation than plasma from sham-operated groups (p < .05). Treatment of IIR plasma with anti-C5a antibody ameliorated the enhanced leukoaggregation characteristic of IIR plasma. Pretreatment with dimethylthiorea and deferoxamine prevented reperfusion-induced activation of complement and inhibited the chemotactic activity of plasma from IIR animals. These data are consistent with the hypothesis that IIR activates complement and that the OH. generated during reperfusion may be one mechanism by which C is activated in this injury model.

Animals↗
PubMed1990

Treatment of transfusional iron overload.

Advances in the treatment of iron overload hold the promise of making long-term transfusion therapy a safer approach to the management of thalassemia major, sickle cell disease, and numerous other hematologic disorders. The responsibility now placed on the treating physician is to monitor iron stores carefully, to begin chelation therapy at an appropriate time, and to encourage regular use of deferoxamine. For the clinical investigator, the success of chelation therapy with deferoxamine should prompt an intensive search for new chelators. These new chelators should be not only effective but also inexpensive, readily available, safe, and easy to administer.

Administration, Oral↗
PubMed1990

Chelation therapy and cardiac status in older patients with thalassemia major.

Cardiac dysfunction is the most common cause of death in patients with homozygous beta-thalassemia. We studied a group of 10 older patients (mean age 17.5 years) with and without preexisting cardiac dysfunction who had begun chelation therapy on the average of 10 years after regular transfusions were initiated. Over the 4-year study period, two patients were noncompliant with deferoxamine therapy. Their clinical status and cardiac function deteriorated, and both died with evidence of arrhythmia and congestive heart failure. The remaining eight patients were compliant. Despite a drop in mean serum ferritin from 3,814 +/- 577 (SE) ng/ml to 1,056 +/- 146 ng/ml (p less than 0.01), two patients with preexisting cardiac problems and one patient without preexisting heart disease developed further abnormalities. Of the three patients whose status declined, one ultimately improved with alternative chelation therapy. These data suggest that for a few older patients, improvement or stabilization of cardiac status may not be achieved with improved compliance and reduced serum ferritin levels. For these patients, new approaches appear to be warranted. On the other hand, we have demonstrated that in most cases, older patients who began chelation therapy years after transfusions began have benefited from compliance with standard subcutaneous deferoxamine regimens.

Adolescent↗
PubMed1996

Erythrocytapheresis can reduce iron overload and prevent the need for chelation therapy in chronically transfused pediatric patients.

PURPOSE: This research was undertaken to determine the advantages, complications, costs, and efficacy of erythrocytapheresis in young pediatric patients who receive chronic erythrocyte transfusion therapy. PATIENTS AND METHODS: We retrospectively analyzed data for 10 children who received erythrocytapheresis for an average of 16 months. Erythrocytapheresis was compared to simple transfusion therapy with respect to annual blood unit exposure, occurrence of alloimmunization, and costs. Serum ferritin levels were compared before and after the period of erythrocytapheresis. RESULTS: Erythrocytapheresis was well tolerated, even in children as young as 5 years or as small as 20 kg. It required a greater annual unit exposure than simple transfusions, but did not increase alloimmunization. Ferritin levels decreased significantly in children receiving concurrent deferoxamine, and decreased or stabilized in those not on chelation therapy. Children started on erythrocytapheresis soon after stroke have not developed iron overload. Although the costs of erythrocytapheresis exceed that of simple transfusion, the substantial costs of deferoxamine therapy should be considered; one child on erythrocytapheresis has been able to discontinue chelation therapy following normalization of his ferritin level. CONCLUSION: Erythrocytapheresis is a safe and effective method for young patients receiving chronic erythrocyte transfusions. Erythrocytapheresis can reduce total iron burden and may obviate the need for expensive chelation therapy.

Adolescent↗
PubMed2004

Energy failure in astrocytes increases the vulnerability of neurons to spreading depression.

A neuroprotective role of astrocytes has been hypothesized, but the mechanism is debated and in vivo evidence is limited. To test this hypothesis, a sublethal stressor (spreading depression) and fluorocitrate (FC), a selective inhibitor of the astrocytic Krebs cycle, were used in urethane-anaesthetized adult rats. Neuronal damage was assessed 24 h after treatment with silver stain and immunoreactivity for a 72-kDa heat-shock protein. ATP levels and mitochondrial aconitase activity, a marker indicating exposure to reactive oxygen species, were measured after 4 and 24 h. Spreading depression alone did not affect ATP levels, mitochondrial aconitase activity, or induce neuronal injury in the cortex. Local or intraventricular injection of FC significantly decreased ATP levels and mitochondrial aconitase activity, but did not produce neuronal damage. In animals receiving injections of FC and then spreading depression, there was evidence of significant neuronal stress and damage. Isocitrate, which bypasses the metabolic inhibition produced by FC, prevented all of the changes seen after the combination of FC and spreading depression. One-hour pretreatment with dimethyl sulfoxide (a scavenger of hydroxyl radicals), deferoxamine (an iron chelator) or fructose-1,6-bisphosphate also blocked inactivation of mitochondrial aconitase, ATP depletion and the neuronal damage induced by FC and spreading depression. These experiments demonstrate that inhibition of the metabolism of astrocytes, with a decrease in ATP levels, will increase the susceptibility of neurons to the stress induced by spreading depression. The neuroprotective effects of dimethyl sulfoxide, deferoxamine and fructose-1,6-bisphosphate suggest that oxidative stress contributes to the neurotoxicity in this situation.

Aconitate Hydratase↗
PubMed1994

Effects of mifepristone (RU-486) on heme metabolism and cytochromes P-450 in cultured chick embryo liver cells, possible implications for acute porphyria.

Mifepristone (RU-486), a potent progesterone receptor antagonist and inducer of cytochromes P-450, is currently in use in Europe, particularly as a post-coital oral contraceptive. Soon it will be available in the United States, as well. Since progesterone has been implicated in the pathogenesis of acute attacks of porphyria, the use of RU-486 or related compounds might be considered in porphyric patients. However, as with other cytochrome P-450 inducers, RU-486 may have the ability to precipitate or exacerbate attacks of acute porphyria. The acute porphyrias in relapse are associated with an increase in activity of delta-aminolevulinic acid synthase, the first and normally rate-controlling enzyme in heme biosynthesis. We have used primary cultures of chick embryo liver cells to test the ability of RU-486 to induce delta-aminolevulinic acid synthase activity and mRNA, cytochromes P-450, porphyrin accumulation, and heme oxygenase. We found that RU-486, at concentrations observed in human plasma after a single oral dose, induced the mRNA and activity of delta-aminolevulinic acid synthase, both by itself and in the presence of deferoxamine, a potent iron chelator that inhibits ferrochelatase. RU-486 and deferoxamine together also produced significant accumulations of protoporphyrin. These results indicate that RU-486 may pose a risk in patients with known acute porphyria and should be used with caution. RU-486 increased the concentration of total cytochrome P-450, and the activity of erythromycin demethylase, an activity specifically catalyzed by cytochrome P-450 3A. Unlike several other porphyrogens (e.g. hydantoins, barbiturates), RU-486 does not produce accumulation of uroporphyrin or induction of heme oxygenase in chick embryo liver cells.

5-Aminolevulinate Synthetase↗