Protoporphyria induced by the orally active iron chelator 1,2-diethyl-3-
hydroxypyridin-4-one in C57BL/10ScSn mice
AG Smith, B Clothier, JE Francis, AH Gibbs, F De Matteis and RC Hider
MRC Toxicology Unit, University of Leicester, United Kingdom.
Administration in the drinking water of the orally-active iron chelator
1,2-diethyl-3-hydroxypyridin-4-one (CP94) to C57BL/10ScSn mice caused the
development of hepatic protoporphyria. This was detected after 1 week and
continued as long as the chelator was given (15 weeks). The more
hydrophilic 1,2-dimethyl- and 1-hydroxyethyl,2-ethyl-analogues (CP20 and
CP102) were also tested, but they were both inactive in inducing
accumulation of protoporphyrin in the liver. Restriction of in vivo iron
supply for ferrochelatase seemed a likely mode of action, but an
approximately 30% decrease in activity of this enzyme was also observed
when measured in vitro. Extracts of livers from mice given CP20, CP94, and
CP102 showed no potential to inhibit mouse ferrochelatase, in contrast to
the findings with an extract from mice treated with the known porphyrogenic
chemical 4-ethyl-3, 5- diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine,
indicating that ferrochelatase inhibition did not occur by the formation of
an N-ethyl- protoporphyrin derived from metabolism by cytochrome P450,
CP20, CP94, CP102, and CP117 (the pivoyl ester of CP102) all caused
significant depression of the levels of ferritin-iron and total nonheme
iron, but only CP94 caused the significant accumulation of protoporphyrin.
Protoporphyria did not occur with iron overloaded C57BL/10ScSn mice or in
SWR mice that had elevated basal iron status. Although the protoporphyrin
had only a small effect on the total levels of the hemoprotein cytochrome
P450 in C57BL/10ScSn mice, the activity of the CYP2B isoforms of cytochrome
P450 was actually induced in both strains. The results show that CP94 could
cause protoporphyria in individuals of low iron status, perhaps through
specifically targeting particular iron pools available to ferrochelatase
and by concomitantly stimulating heme synthesis.
Volume 89,
Issue 3,
pp. 1045-1051,
02/01/1997
Copyright © 1997 by The American Society of Hematology
