Biliary iron excretion in rats following treatment with analogs of pyridoxal isonicotinoyl hydrazone.
نویسندگان
چکیده
Iron overload is a major life-threatening complication of thalassemia major and other iron-loading anemias treated by regular blood transfusions. Although the clinical manifestations of iron overload may be prevented by desferrioxamine, the only iron-chelating drug in routine clinical use, this treatment requires subcutaneous infusion of desferrioxamine for 12 hours each day. New orally effective iron chelators are urgently needed, and pyridoxal isonicotinoyl hydrazone (PIH), which was first recognized as an effective iron chelator in vitro and subsequently in vivo, shows promise for the treatment of iron overload. More recently, over 40 analogs of PIH were synthesized, and some of them proved to be very potent in mobilizing 59Fe in vitro from 59Fe-labeled cells. In this study, we show that PIH analogs such as pyridoxal benzoyl hydrazone, pyridoxal p-methoxybenzoyl hydrazone (PMBH), pyridoxal m-fluorobenzoyl hydrazone (PFBH), and pyridoxal-2-thiophenecarboxyl hydrazone, compounds previously shown to mobilize iron from cells in vitro, are also effective in vivo. All of these chelators significantly enhanced biliary excretion of iron (measured by atomic absorption spectrophotometry) following their intraperitoneal (IP) and/or oral administration to rats. The most effective was PFBH, which increased iron concentration in the bile about 150-fold, as compared with basal biliary iron concentration, within 1 hour following a single IP dose of 0.2 mmol/kg body weight. In contrast, desferrioxamine increased the biliary iron concentration only 20-fold to 30-fold under the same conditions. Moreover, while control rats excreted approximately 0.8 microg Fe in 2 hours, treatment with PFBH, PMBH, and desferrioxamine resulted in cumulative excretions of 87, 59, and 22 microg Fe, respectively, in the same period of time. Interestingly, PMBH was also quite effective following gastric administration, resulting in a 6-hour cumulative value of 34 microg Fe. These compounds are nontoxic and are inexpensive and easy to make. Their further evaluation as candidate drugs for the treatment of iron overload is warranted.
منابع مشابه
Effects of combined chelation treatment with pyridoxal isonicotinoyl hydrazone analogs and deferoxamine in hypertransfused rats and in iron-loaded rat heart cells.
Although iron chelation therapy with deferoxamine (DFO) results in improved life expectancy of patients with thalassemia, compliance with parenteral DFO treatment is unsatisfactory, underlining the need for alternative drugs and innovative ways of drug administration. We examined the chelating potential of pyridoxal isonicotinoyl hydrazone (PIH) analogs, alone or in combination with DFO, using ...
متن کاملEffects of Combined Chelation Treatment with Pyridoxal Isonicotinoyl Hydrazone (PIH) Analogs and Deferoxamine in Hypertransfused Rats and in Iron-Loaded Rat Heart Cells Running Head: Combined PIH analog and DFO Chelation Treatment Heading: Red Cells
Gabriela Link , Prem Ponka, Abraham M Konijn, William Breuer, Z Ioav Cabantchik and Chaim Hershko . Department of Human Nutrition and Metabolism, Hebrew University Hadassah Medical School, Department of Biological Chemistry, Institute of Life Sciences, and Department of Medicine, Shaare Zedek Medical Center, Hebrew University of Jerusalem , Jerusalem, Israel and Lady Davis Institute for Medical...
متن کاملCytotoxic analogs of the iron(III) chelator pyridoxal isonicotinoyl hydrazone: effects of complexation with copper(II), gallium(III), and iron (III) on their antiproliferative activities.
This study examined if complexation with metals increased the antiproliferative activities of chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class. Addition of iron(III) to some PIH analogs markedly depressed their activities, whereas it had little effect on others. The gallium(III) complex of PIH, but not its copper(II) complex, was more efficient than the apochelator at inhibiting [...
متن کاملA lipophilic iron chelator can replace transferrin as a stimulator of cell proliferation and differentiation
Of the different growth supplements used in chemically defined media, only transferrin is required for differentiation of tubules in the embryonic mouse metanephros. Since transferrin is an iron-carrying protein, we asked whether iron is crucial for tubulogenesis. Differentiation of metanephric tubules both in whole embryonic kidneys and in a transfilter system was studied. The tissues were gro...
متن کاملPotent antimycobacterial activity of the pyridoxal isonicotinoyl hydrazone analog 2-pyridylcarboxaldehyde isonicotinoyl hydrazone: a lipophilic transport vehicle for isonicotinic acid hydrazide.
The rise in drug-resistant strains of Mycobacterium tuberculosis is a major threat to human health and highlights the need for new therapeutic strategies. In this study, we have assessed whether high-affinity iron chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class can restrict the growth of clinically significant mycobacteria. Screening a library of PIH derivatives revealed that one...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Blood
دوره 91 11 شماره
صفحات -
تاریخ انتشار 1998