phosphorus-radioisotopes and Hemochromatosis

In the human metal storage disorders of Wilson's disease and primary haemochromatosis, ion transport and excretion dysfunctions result in the intracellular deposition of copper and iron, respectively. These aberrant accumulations of transition metal ions lead to extensive tissue damage, especially in the liver. In order to investigate the possible role of metal ion-mediated oxygen free radical-generated DNA damage in these processes, DNA was isolated from liver of eight Wilson's disease patients and six haemochromatosis patients. Significant levels of bulky DNA damage were detected in these samples by 32P-postlabelling analysis, but were not found in liver DNA from age-matched controls. This form of novel DNA damage was detected in six out of eight Wilson's patients, varying between approximately 1 and 100 base modifications per 10(8) nucleotides, and in all of the haemochromatosis samples examined; the levels of modified species per 10(8) nucleotides varying from approximately 2 to 50. HPLC analysis of these bulky DNA lesions demonstrated that the species formed in Wilson's disease and in haemochromatosis were chromatographically identical but were not the same as putative purine dimers that can be generated in DNA by in vitro incubation with Cu+/Fe2+ and H2O2 (although the possibility that the adducts detected are closely related has not been ruled out). Analysis of the oxidative base lesion 8-hydroxydeoxyguanosine showed that levels were not elevated in liver DNA from either Wilson's disease or haemochromatosis sufferers. In fact, a statistically significantly lower level of this lesion was found in Wilson's disease patients than in controls. These data suggest that bulky DNA damage present in the liver of both wilson's disease and primary haemochromatosis patients may play a more important role in the induction of tissue damage than 8-hydroxydeoxyguanosine. The novel DNA damage detected by 32P-poslabelling may also be a significant factor in the initiation of neoplasia leading to malignant hepatoma in haemochromatosis patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Child; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Copper; Deoxyguanosine; DNA Adducts; Female; Free Radicals; Hemochromatosis; Hepatolenticular Degeneration; Humans; Hydrogen Peroxide; Iron; Liver; Male; Middle Aged; Oxidative Stress; Phosphorus Radioisotopes; Purine Nucleotides; Statistics, Nonparametric

Topics: Adult; Aged; Body Burden; Chromium Radioisotopes; Copper; Female; Half-Life; Hemochromatosis; Hepatolenticular Degeneration; Humans; Male; Middle Aged; Phosphorus Radioisotopes; Radioisotopes; Time Factors; Whole-Body Counting

Radionuclide studies of the erythron are valuable to the physician in evaluating the clinical situation in a wide variety of hematologic disorders. A complete and accurate analysis of the life cycle of the red cell can be obtained with a full iron kinetic study, in conjunction with a DF32P red-cell survival study. However, a complete iron kinetic study is not always necessary. It may be abbreviated by deleting the in vitro phase of the iron kinetic procedure. The abbreviated iron kinetic study is also done in conjunction with a DF32P red-cell survival study. It can easily be performed by injecting 59Fe-labeled plasma and monitoring externally over the spleen, liver, and sacrum. Measurements of red-cell survival may be obtained with either 51Cr or DF32P. Although 51Cr provides a relatively uniform label of circulating red cells and is convenient to count in vitro, its highly variable elution rate precludes an accurate measurement of erythrocyte survival. The 51Cr method provides only a rough index of circulating red-cell half-times as a measure of red-cell survival. DF32P, HOWEVER, IS A PERMANENT LABEL OF CIRCULATING RED CELLS. It provides a direct measurement of erythrocyte survival and permits in vivo labeling of red cells simply by means of direct intravenous injection. Because it has an elution rate that is virtually zero after minimal elution on the day of injection, and because it is not reutilized, DF32P is unquestionably the best agent known for the determination of red-cell survival. In addition to these diagnostic data, the complete iron kinetic study can provide data on the deposition of iron in storage and the rate of iron storage exchange. It can also determine if erythropoiesis is quantitatively abnormal and if the abnormality is located in the bone marrow or in other organs such as the liver or spleen. Although the study of hematologic disorders is one of the most rapidly developing areas of medical research, techniques that are currently available can provide an understanding of the life cycle of the red cell and valuable data that can be applied directly to the clinical situation. When performed accurately, these studies provide a thorough analysis of the pathophysiology of the erythron and are valuable clinical tools that can be used successfully in the diagnosis and evaluation of a broad spectrum of hematological disorders.

Topics: Anemia; Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Anemia, Hypochromic; Anemia, Pernicious; Bone Marrow Diseases; Cell Survival; Chromium Radioisotopes; Erythrocytes; Hemochromatosis; Hemoglobinuria, Paroxysmal; Hemosiderosis; Humans; Iron Radioisotopes; Isoflurophate; Isotope Labeling; Leukemia; Phosphorus Radioisotopes; Polycythemia Vera; Primary Myelofibrosis; Radioisotopes; Radionuclide Imaging; Spherocytosis, Hereditary; Splenic Diseases; Vitamin E Deficiency