Subject(s)
Toxicity Tests/methods , Administration, Oral , Animals , Female , Guidelines as Topic , Lethal Dose 50 , MaleABSTRACT
To date, there has been no effective therapy to counter incorporated radionuclides of strontium. In an endeavour to solve this problem, we have synthesized and evaluated various N,N'-disubstituted derivatives of 1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane(crypt and 2.2) for their ability to mobilize 85Sr2+. These ligands are water soluble and have a relatively low acute i.v. toxicity, as demonstrated by their evaluation in rat and mouse. The di-sodium-calcium complex and tetra-sodium salt of the cryptand (2.2) dimalonate have exerted a remarkable decorporation effectiveness for 85Sr2+ in extracellular space. The tetra-potassium salt of the cryptand (2.2) dimalonate has a moderate effect, while no mobilization activity can be detected with the cryptand (2.2) that does not have a side chain substituent. Animals were initially given 85SrCl2 either i.p. or into the lung, then the compounds were administered 30-60 min later using an alternative route. The degree of decorporation achieved a 80-95% of the initial body burden (ibb) compared with the control values of 20-30%. The agents are resorbed easily from the lung, and the radiostrontium deposition in bone was inhibited strongly by a decorporation agent. The success of the treatment, however, is dependent upon the speed with which decorporation therapy commences.
Subject(s)
Crown Ethers , Ethers, Cyclic/chemistry , Strontium Radioisotopes/chemistry , Animals , Chelating Agents , Female , Male , Metabolic Clearance Rate , Mice , Rats , Rats, Wistar , Strontium Radioisotopes/pharmacokineticsABSTRACT
The radioprotective agent WR-2721 is dephosphorylated to the free thiol form WR-1065 in vivo. The effects of WR-2721, WR-1065 and reduced glutathione on a mitochondrial lipid peroxidation system were compared. WR-2721 had no effect on mitochondrial lipid peroxidation in vitro, and could not prevent the inactivation of mitochondrial enzymes. Both WR-1065 and glutathione were effective inhibitors of mitochondrial lipid peroxidation induced by ADP/Fe/NADPH or by ADP/Fe/ascorbate. Both thiols correspondingly delayed the free radical-mediated inactivation of succinate dehydrogenase and isocitrate dehydrogenase. WR-1065 was able to reduce cumene hydroperoxide non-enzymatically, and proved to be weak substrate for glutathione peroxidase. The disulfide formed from WR-1065 could be reduced by glutathione without the participation of glutathione reductase. A redox cycle is proposed between WR-1065, glutathione and glutathione reductase to explain the inhibitory effect of WR-1065 on lipid peroxidation.
Subject(s)
Amifostine/pharmacology , Lipid Peroxidation/drug effects , Mercaptoethylamines/pharmacology , Mitochondria, Liver/metabolism , Organothiophosphorus Compounds/pharmacology , Radiation-Protective Agents/pharmacology , Animals , Benzene Derivatives/pharmacology , Free Radicals , Glutathione/metabolism , Glutathione/pharmacology , Glutathione Reductase/metabolism , In Vitro Techniques , Isocitrate Dehydrogenase/metabolism , Male , Mice , Mitochondria, Liver/drug effects , Mitochondria, Liver/enzymology , Succinate Dehydrogenase/metabolismABSTRACT
The degree of mitochondrial ADP/Fe/NADPH-induced lipid peroxidation was increased up to the fourth day after 9.0 Gy whole body gamma-irradiation. The lipid peroxidation inhibiting effect of succinate added to isolated mitochondria was diminished as a consequence of irradiation. The succinate, administered in vivo prior to irradiation, decreased the amount of malondialdehyde production and protected the succinate dehydrogenase enzyme against inactivation. The mean survival of succinate-pretreated animals was much longer than that of controls. The role of mitochondrial lipid peroxidation in the pathogenesis of radiation injury is discussed.
Subject(s)
Lipid Peroxides/metabolism , Mitochondria, Liver/metabolism , Radiation-Protective Agents , Succinates/pharmacology , Adenosine Diphosphate/metabolism , Animals , Gamma Rays , Male , Malondialdehyde/biosynthesis , NAD/metabolism , Rats , Succinate Dehydrogenase/metabolismABSTRACT
Succinate inhibits NADPH-dependent lipid peroxidation of liver mitochondria. This effect of succinate decreased 12 h after whole-body 60Co-gamma irradiation, depending on the dose of irradiation.
Subject(s)
Cobalt Radioisotopes , Lipid Peroxides/metabolism , Mitochondria, Liver/radiation effects , Succinates/pharmacology , Animals , Dose-Response Relationship, Radiation , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Microsomes, Liver/radiation effects , Mitochondria, Liver/drug effects , Mitochondria, Liver/metabolism , Rats , Succinic AcidABSTRACT
The effect of sublethal (6.0 Gy) and LD50/30 (9.0 Gy) doses of 60Co-gamma-irradiation on malondialdehyde (MDA) level was studied in rats. The findings suggest that in the organs investigated (brain, liver, spleen, kidney, testicle, stomach, small intestines) acute 60Co-gamma-irradiation increased the formation of MDA, the main product of lipid peroxidation, in a time-related manner to an extent characteristic of the organ investigated. Differences in the degree and temporal development of the changes allow some conclusions as to the radiosensitivity of individual organs. On this basis it can be assumed that the increase in MDA level caused by irradiation considerably contributes to the development of certain symptoms of radiation sickness.
