The long-term goal is to identify orally effective aluminum chelators with sufficient selectivity for Al and safety in animals to warrant testing in humans for the prevention and treatment of Al accumulation disorders. An ideal Al chelator will overcome the limitations of desferrioxamine, namely lack of oral efficacy, its relatively high cost and toxicity. Al accumulation results from parenteral administration of pharmaceuticals, prolonged consumption of Al-based phosphate binders by the renally impaired and exposure of industrial workers to Al fumes. The role of Al in Alzheimer's disease and other dementing disorders is under investigation and is controversial. A safe Al chelator with continued efficacy may help determine the role of Al in these diseases.
The specific aim of the present application is to test the hypothesis that systemic availability, efficacy and safety of Al chelators relates to the lipophilicity of the chelator and the Al-chelator complex results in Al mobilization from storage sites to safely induce Al elimination and reduce Al toxicity. Eight analogs of 3-hydroxypyridin-4-one, a family of orally effective metal chelators, will be studied. Their lipophilicity ranges from below to above the hypothesized ideal range. The oral bioavailability of each analog will be quantitated in rabbits to determine the relationship between lipophilicity and absorption. The analogs will be tested in a single dose iv study in Al-loaded rabbits to determine in vivo Al chelation activity, evidenced by increased serum Al and biliary or urinary Al output. Selected orally absorbed analogs that increase Al elimination will be repeatedly administered to Al-loaded rabbits to ascertain their continued oral Al chelation efficacy as evidenced by increased Al elimination after repeated treatment and decreased tissue Al. Safety and ability to reverse Al-induced toxicity will be assessed by histopathological, hematological and bone histological and histomorphometric measurements. Specificity of Al chelation will be assessed by multiple element analysis of selected fluids and tissues. Efficacy and safety results will be correlated to lipophilicity to identify the optimal lipophilicity of the 3-hydroxypyridin-4-ones. The results may identify compounds that warrant testing in humans and will strongly guide the future design and selection of structurally dissimilar compounds as potential Al chelators.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Medicine
United States
Zip Code
Hong, C B; Fredenburg, A M; Dickey, K M et al. (2000) Glomerular lesions in male rabbits treated with aluminium lactate: with special reference to microaneurysm formation. Exp Toxicol Pathol 52:139-43
Yokel, R A; O'Callaghan, J P (1998) An aluminum-induced increase in GFAP is attenuated by some chelators. Neurotoxicol Teratol 20:55-60
Yokel, R A; Meurer, K A; Hong, C B et al. (1997) Short-term oral 3-hydroxypyridin-4-one dosing increases aluminum excretion and partially reverses aluminum-induced toxicity in the rabbit independent of chelator lipophilicity. Drug Metab Dispos 25:182-90
Yokel, R A (1996) Aluminum chelation by 3-hydroxypyridin-4-ones in the rat demonstrated by microdialysis. Biol Trace Elem Res 53:193-203
Xie, C X; Mattson, M P; Lovell, M A et al. (1996) Intraneuronal aluminum potentiates iron-induced oxidative stress in cultured rat hippocampal neurons. Brain Res 743:271-7
Skinner, T L; Meurer, K A; Yokel, R A (1996) HPLC quantitation of a very hydrophilic 3-hydroxypyridin-4-one chelator using a simple separation procedure and the baseline file subtraction method. J Chromatogr Sci 34:52-7
Xie, C X; Yokel, R A (1996) Aluminum facilitation of iron-mediated lipid peroxidation is dependent on substrate, pH and aluminum and iron concentrations. Arch Biochem Biophys 327:222-6
Yokel, R A; Meurer, K A; Skinner, T L et al. (1996) The 3-hydroxypyridin-4-ones more effectively chelate aluminum in a rabbit model of aluminum intoxication than does desferrioxamine. Drug Metab Dispos 24:105-11
Allen, D D; Orvig, C; Yokel, R A (1995) Evidence for energy-dependent transport of aluminum out of brain extracellular fluid. Toxicology 98:31-9
Xie, C X; St Pyrek, J; Porter, W H et al. (1995) Hydroxyl radical generation in rat brain is initiated by iron but not aluminum, as determined by microdialysis with salicylate trapping and GC-MS analysis. Neurotoxicology 16:489-96

Showing the most recent 10 out of 12 publications