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Title: Determinants of removal and reappearance in plasma non-transferrin bound iron
Author: Srichairatanakool, Somdet
ISNI:       0000 0001 3475 9486
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2000
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Transferrin is a plasma iron transport protein responsible for binding iron released from the breakdown of red cells in macrophages and delivering this iron to developing red cells in the bone marrow. In health, about one-third of the two iron binding sites on transferrin molecules are saturated with iron. In iron overload, transferrin becomes fully saturated and iron is found in the plasma in forms which are not bound to transferrin, defined as nontransferrin bound iron (NTBI). In this thesis, the factors which determine the appearance and removal of NTBI have been examined. The effects of iron chelation therapy with desferrioxamine (DFO) have been compared both in vivo and in vitro. In order to do this, a novel modification of an existing HPLC based assay system has been developed. This assay has been designed following the discovery during the work on this thesis of an in vitro 'shuttle' effect of iron between nitrilotriacetic acid (NTA) and DFO. This 'shuttle' leads to a falsely low measurement of NTBI, or a falsely fast apparent kinetic of NTBI removal, unless the free metal binding sites on DFO are blocked prior to the assay procedure. An aluminium blocking step has been developed whereby the remaining metal binding sites of DFO are blocked with an excess of aluminium prior to the NTBI assay. Using this approach, the kinetics of NTBI removal by DFO in vitro are relatively slow as is NTBI removal in vivo. NTBI removal by DFO is both concentration and time dependent but in iron overload NTBI removal is not complete at 10 μM DFO (a clinically relevant plasma concentration) even after 8 hours. Having defined the aluminium blocking method in vitro, the kinetics of NTBI removal by a variety of clinical DFO regimens has been examined. DFO levels have also been measured using a novel immunoassay system which measures the iron bound form of DFO, namely ferrioxamine (FO). The removal of NTBI with 8 hour subcutaneous infusions of DFO (standard therapy) has been compared with NTBI removal with twice daily intramuscularly DFO boluses. Surprisingly, these studies suggest that NTBI removal as quantitated by reduction in the area under the curve is as efficient with the bolus regimen as 8 hour subcutaneous infusions. The kinetics of NTBI removal have been also examined with prolonged intravenous DFO therapy and suggest that NTBI removal may not be possible with conventional intravenous therapy. In a further study, the kinetics of removal with long acting depot DFO have been compared with NTBI removal with conventional therapy. The effects of a novel polymeric form of DFO (HES- DFO) on NTBI removal have been examined which suggest that this form of DFO may result in significant quantities of loosely bound and potentially toxic forms of iron building up in plasma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available