Effects of desferrithiocin and its derivatives on peripheral iron and striatal dopamine and 5-hydroxytryptamine metabolism in the ferrocene-loaded rat.
Iron overload disorders, such as beta-thalassaemia, are currently treated with the iron chelator desferrioxamine (DFO) or 1,2-dimethyl-3-hydroxypyridin-4-one (L1), which is currently under clinical evaluation. However, DFO is inactive orally and needs to be administered by intramuscular infusion, whilst there are concerns over the long-term effectiveness and toxicity of L1. In addition, both DFO and L1 affect brain dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolism. In this study, the 3,5,5-trimethylhexanoyl ferrocene rat model of iron overload was used to compare the iron-chelating capabilities of a novel orally active siderophore, desferrithiocin (DFT) and its desmethyl derivatives DFT-D and DFT-L, to that of DFO, along with their ability to affect brain DA and 5-HT metabolism. Chronic administration of ferrocene produced a 12-fold increase in liver iron levels, as assessed by electrothermal atomic absorption. Subsequent treatment with DFT over a two-week period produced a 37% reduction in liver iron levels, whereas similar treatment with DFT-D and DFT-L produced a more marked reduction in these levels (65% and 59%, respectively) in the ferrocene-treated animals. In contrast, using the same dosing regimen, DFO and L1 only produced a 16% and 18% reduction, respectively, in liver iron levels. Both DFT and its derivatives failed to affect either striatal DA or 5-HT metabolism when assessed by HPLC. In view of the previously described oral bioavailability of DFT, the marked ability of DFT and its derivatives to chelate hepatic iron, and their inability to affect brain DA or 5-HT metabolism, such siderophores appear potentially useful clinical iron chelators.
Dexter
D T
DT
Department of Neurodegenerative Disorders, Imperial College School of Medicine, London, UK. d.dexter@ic.ac.uk
Ward
R J
RJ
Florence
A
A
Jenner
P
P
Crichton
R R
RR
D000284:Administration, Oral; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004095:Dihydropyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D005296:Ferrous Compounds; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D019190:Iron Overload / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D000075163:Metallocenes; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D004095:Dihydropyridines; D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D000075163:Metallocenes; D013844:Thiazoles; D012701:Serotonin; D007501:Iron; C004998:ferrocene; C050223:desferrithiocin; D004298:Dopamine