|Title||Free Radical Mechanism of Iron Toxicity Effects of Iron Chelators and Antioxidants|
|Author||L.Korkina; I. Deeva; I. Afanas;ev; P. Trakhtman; A. Maschan|
|Publisher||8th International Conference: Oral Chelation in the Treatment of Thalassemia and other Diseases|
PLZENSKY LEKARSKY SBORNIK Supplementum 71 1996: 73-76
FREE RADICAL MECHANISM OF IRON TOXICITY
L. B. Afanas’ev, L. I. Afanas’ev, E. A. Ostrachovich, I. B. Deeva, and L. G. Korkina
Vitamin Research Institute and Russian Institute of Pediatric Hematology. Moscow. Russia
Recent studies demonstrate an importance of free radical-mediated iron toxicity. It is believed that its major mechanism is iron-catalyzed decomposition of hydrogen peroxide to form hydroxyl radical the Fenton reaction. Such a mechanism suggests that chelators, have been earlier regarded only as the agents capable of accelerating iron excretion may acquire additional anti -or prooxidant properties depending on the ability of iron-chelator complex to catalyze or suppress the Fenton reaction. Thus, chelators may suppress iron toxicity without accelerating iron excretion if they form the iron-chelator complexes inactive in the Fenton reaction.
In this work we have studied the effects of an oral chelator, 1-allyl-2-methy-3-hydoroxy-4-pyridinone (AMHP), and two natural antioxidants possessing chelating properties, bioflavonoid rutin (vitamin P) and lipoic (LA, on in vitro and in vivo free radical-mediated damaging processes. We found that all the above compounds were able to chelate iron ions. While the structure of iron-rutin complex (? max 400-420 nm) remains uncertain, spectrophotometric and ESR studies proved the formation of Fe (III) (AMHP) 2 (2max453 nm g-factor4.3) and Fe (II) (DHLA) 2 (2max 590-620 nm. DHLA is dihydroxylipoic acid) complexes. The formation of iron – rutin complex was not accompanied by the generation of oxygen radicals, and this complex was inert in liposomal lipid peroxidation . ·In contrast, the chelation of iron ions by AMHP or LADHLA resulted in the formation of superoxide ion depending on the iron valency. Thus, under anaerobic conditions AMHP formed a strong 2:1 iron complex (LgK 8.33 M2) with ferric ions, under the same conditions. AMHP did not react with ferrous ions but oxidized them in the presence of molecular oxygen forming an identical ferric complex
THE EFFECTS OF NATURALLY OCCURRING ANTIOXIDANTS AND IRON CHELATORS ON THE OXIDANT/ANTIOXIDANT BALANCE IN THE ERYTHROCYTES AND LEUKOCYTES OF THALASSEMIA PATIENTS
Korkjna Ludmila1, Deeva Irina1, Afanas ‘ev Ilia2, Ostrachovitch Elena2, and Afanas ‘ev Igor3
1 Russian State Medical University, Moscow, Russia, 2 Institute of pharmacology, Moscow, Russia; 3 Vitamin Research institute, Moscow, Russia
It is reported in a number of works that patients suffering from β-thalassemia are subjected to in vivo oxidative stress due to the excessive production of reactive oxygen species (ROS) by the reaction of abnormal hemoglobin with molecular oxygen. The crucial role of “free” iron ions bound to the membrane of β-thalassemic erythrocytes in the generation of hydroxyl radicals has also been shown. On these grounds, the application of iron chelators as essential part of the conventional therapy of iron-overload patients is thought to be relevant both in terms of iron removal from the body and accelerated discharge of ROS from these erythrocytes. To our knowledge, little is known about the capacity of circulating white blood cells (WBC) of patients with β-thalassemia to produce ROS or the effects of iron ions on WBC ROS-production and on its antioxidant enzymes. In this study, the erythrocytes of patients with β-thalassemia (major and intermediate) and of β -thalassemia gene carriers were found to produce more superoxide ions than the normal ones, either spontaneously or through induction by different quinones. This enhanced production of superoxide ion was stoichiometrically connected with methemoglobin formation and GSH oxidation. These three reactions were inhibited by iron chelators (Desferal and Deferipron) and by natural non-toxic antioxidants with chelating properties such as bioflavonoid rutin and Bio-Normalizer®, a functional food produced by the fermentation of papaya fruits. The ROS production by the WBC of β-thalassemic homo- and heterozygotes was markedly decreased in comparison with donor WBC. However, the sharp increase in the intracellular generation of ROS may have resulted from either an in vitro WBC incubation or the treatment of patients with iron chelators. Elevation in the level of intracellular ROS may be due to the activation of WBC NADPH-oxidase and a decrease of SOD and catalase activities in WBC acted upon by iron chelators. On the other hand, both the antioxidants rutin and Bio-Normalizer suppressed the excessive production of ROS in the WBC of thalassemia patients in a concentration-dependent manner. Both the iron chelators and the natural antioxidants studied substantially enhanced the total antioxidant capacity of the plasma of thalassemic patients. These findings led us to suggest that a combination of iron chelators and antioxidants might be useful in protecting the erythrocytes and WBC of β-thalassemic patients against oxidative stress associated with genetic defect and iron chelation.
REALIZATION OF TREATMENT WITH DEFEROXAM
IN TALASSEMIA MAJOR
Chang Lichun, Fan Yuhuan.
Department of Padiatrics, Redcross Hospital,To No. I Zhenhua Road, Shenzhen, Guangdong, 518031 PR.China
Object Deferoxam was used to treat thalassemia major with transfusion-dependent iron-load, in order to avoid hematochromalosis.
Method Deferoxam (Desferal, DFO) manufactured by Swiss was administer by intravenous injection, 30 ~ 50mg/kg/day, 1 to 3 days continuously, to control serum ferroprotein under 1000mg/L.
Result Six β-thalassemia majors with long-term blood transfusion (a half years to three years) were treated with DFO, all of them kept normal growth and development without abnormal function of liver and renal.
Conclusion Iron overload in the body is the main pathology of thalassemia major, it requires regular blood transfusions; hematochromalosis is the complication in such patients, left unchecked and without administrating DFO , growth and development will be affected seriously.
A SURVEY OF IRON STATUS IN THALASSEMIA
Youngrong La,i Yu ying Lu, Guifang, et al
The First Affiliated Hospital of Guangxi Medical University, Nanning. Guangxi, PR. China 530021
Object To investigate the iron status in thalassemia patients in Guangxi.
Methods We studied 77 patients with β- thalassemia, 34 patients with hemoglobin H disease and 45 normal subjects. Serum ferritin (SF), free erythrocyte protoprophyrin (FEP), serum iron (SI), total iron-binding capacity (TIBC) and hemoglobin (HB) were determined.
Result The levels of SF, in 65 patients with β-thalassemia heterozygous were not different with those in the normal subjects (p>0.05). Iron deficiency was
The 2nd International Conference on Thalassemia
in China Thalassemia in Millennium
Program & Abstracts
October 13- 16, 1998
Nanning Guangxi, The People’s Republic of China
GUANGXI MEDICAL UNIVERSITY, NANNING, GUANGXI, P.R.CHINA AND THALASSEMIA RESEARCH CENTER, INSTITUTE OF SCIENCE AND TECHNOLOGY FOR RESEARCH AND DEVELOPMENT, MAHIDOL UNIVERSITY, BANGKOK, THAILAND
GOVERNMENT OF GUANGXI ZHUANG AUTONOMOUS REGION NATIONAL RESEARCH COUNCIL OF THAILAND