PROTOPORPHYRIA INDUCED BY THE ORALLY-ACTIVE IRON CHELATOR 1,2-DIETHYL-3-HYDROXYPYRIDIN-4-ONE IN C57BL 10SCSN MICE/

Administration in the drinking water of the orally-active iron chelato r 1,2-diethyl-3-hydroxypyridin-4-one (CP94) to C57BL/10ScSn mice cause d 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 (C P20 and CP102) were also tested, but they were both inactive in induci ng 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 observ ed when measured in vitro. Extracts of livers from mice given CP20, CP 94, and CP102 showed no potential to inhibit mouse ferrochelatase, in contrast to the findings with an extract from mice treated with the kn own porphyrogenic chemical diethoxycarbonyl-2,6-dimethyl-1,4-dihydropy ridine, indicating that ferrochelatase inhibition did not occur by the formation of an N-ethyl-protoporphyrin derived from metabolism by cyt ochrome P450. CP20, CP94, CP102, end 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 C 57BL/10ScSn mice or in SWR mice that had elevated basal iron status. A lthough 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 ind ividuals of low iron status, perhaps through specifically targeting pa rticular iron poets available to ferrochelatase and by concomitantly s timulating heme synthesis. (C) 1997 by The American Society of Hematol ogy.