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Origin and fate of iron mobilized by the 3-hydroxypyridin-4-one oral
chelators: studies in hypertransfused rats by selective radioiron probes of
reticuloendothelial and hepatocellular iron stores
S Zevin, G Link, RW Grady, RC Hider, HH Peter and C Hershko
Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.
The mechanism of in vivo iron chelation by 3-hydroxypyridin-4-ones (CP
compounds) was studied in hypertransfused rats in which the major storage
iron pools in hepatocytes and in the reticuloendothelial (RE) system have
been labeled by selective radioiron probes. Both dimethyl-3-
hydroxypyridin-4-one (CP 20 or L1) and diethyl-3-hydroxypyridine-4-one (CP
94) have an identical and very high (log beta 3 36) binding constant and
selective affinity to iron(III), but the lipid solubility of CP 94 is
considerably higher than that of CP 20. Both chelators induced an increase
in the fecal excretion of hepatocellular iron with no effect on urinary
excretion. In contrast, about one third to one half of the iron mobilized
from RE cells was excreted in the urine. The chelating efficiency of CP 20
was comparable with that of deferoxamine (DF), whereas CP 94 was up to
eight times more effective than DF. Unlike DF, which had no effect by the
oral route, the oral and parenteral effectiveness of both CP compounds was
identical. These findings indicate that: (1) lipid solubility is an
important determinant of in vivo chelating efficiency; (2) urinary iron
excretion induced by the CP compounds is derived from RE cells; (3) part of
the iron mobilized from RE cells and all of the iron derived from
hepatocytes is excreted through the bile; and (4) contrary to previous
observations in cell cultures, there is no in vivo evidence for a
diminishing chelating efficiency at the lowest doses used.
Volume 79,
Issue 1,
pp. 248-253,
01/01/1992
Copyright © 1992 by The American Society of Hematology
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