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 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.
Smith
A G
AG
MRC Toxicology Unit, University of Leicester, United Kingdom.
Clothier
B
B
Francis
J E
JE
Gibbs
A H
AH
De Matteis
F
F
Hider
R C
RC
D000284:Administration, Oral; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D005294:Ferrochelatase / Q000037:antagonists & inhibitors; D006418:Heme / Q000096:biosynthesis; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017094:Porphyrias, Hepatic / Q000139:chemically induced* / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage / Q000633:toxicity*
D007502:Iron Chelating Agents; D011728:Pyridones; C068543:1,2-diethyl-3-hydroxypyridin-4-one; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D005294:Ferrochelatase