Effect of iron and ascorbate on uroporphyria in ascorbate-requiring mice as a model for porphyria cutanea tarda.
Excess hepatic iron is known to enhance both porphyria cutanea tarda (PCT) and experimental uroporphyria. Since previous studies have suggested a role for ascorbate (AA) in suppressing uroporphyria in AA-requiring rats (in the absence of excess iron), the present study investigated whether AA could suppress uroporphyria produced by excess hepatic iron. Hepatic URO accumulation was produced in AA-requiring Gulo(-/-) mice by treatment with 3,3',4,4',5-pentachlorbiphenyl, an inducer of CYP1A2, and 5-aminolevulinic acid. Mice were administered either sufficient AA (1000 ppm) in the drinking water to maintain near normal hepatic AA levels or a lower intake (75 ppm) that resulted in 70 % lower hepatic AA levels. The higher AA intake suppressed hepatic URO accumulation in the absence of administered iron, but not when iron dextran (300-500 mg Fe/kg) was administered. This effect of iron was not due to hepatic AA depletion since hepatic AA content was not decreased. The effect of iron to prevent AA suppression of hepatic URO accumulation was not observed until a high hepatic iron threshold was exceeded. At both low and high AA intakes, hepatic malondialdehyde (MDA), an indicator of oxidative stress, was increased three-fold by high doses of iron dextran. MDA was considerably increased even at low iron dextran doses, but without any increase in URO accumulation. The level of hepatic CYP1A2 was unaffected by either AA intake.


CONCLUSIONS
In this mouse model of PCT, AA suppresses hepatic URO accumulation at low, but not high hepatic iron levels. These results may have implications for the management of PCT.
Gorman
Nadia
N
VA Medical Center, White River Junction, VT 05009, USA.
Zaharia
Adrian
A
Trask
Heidi S
HS
Szakacs
Juliana G
JG
Jacobs
Nicholas J
NJ
Jacobs
Judith M
JM
Balestra
Dominic
D
Sinclair
Jacqueline F
JF
Sinclair
Peter R
PR
D000622:Aminolevulinic Acid; D000818:Animals; D001205:Ascorbic Acid / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D001206:Ascorbic Acid Deficiency / Q000235:genetics / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D007505:Iron-Dextran Complex / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D011078:Polychlorinated Biphenyls; D017119:Porphyria Cutanea Tarda / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D014578:Uroporphyrins / Q000378:metabolism*
D014578:Uroporphyrins; D000622:Aminolevulinic Acid; D007505:Iron-Dextran Complex; D011078:Polychlorinated Biphenyls; D007501:Iron; D019388:Cytochrome P-450 CYP1A2; D001205:Ascorbic Acid; C023035:3,4,5,3',4'-pentachlorobiphenyl