Repression of ALA synthase by heme and zinc-mesoporphyrin in a chick embryo liver cell culture model of acute porphyria.
We characterize a liver cell culture model for acute hepatic porphyrias that recapitulates the biochemical features of the human syndrome. In chick embryo liver cells in primary culture exposed to glutethimide and 4,6-dioxoheptanoic acid, heme alone produced a transient dose-dependent decrease in delta-aminolevulinate synthase and a concomitant increase in heme oxygenase. The addition of low concentrations of zinc-mesoporphyrin (50-200 nM), an inhibitor of heme oxygenase, led to more prolonged decreases in activity of the synthase and to an additive effect with heme. These effects of zinc-mesoporphyrin were associated with prolonged inhibition of heme oxygenase. These results suggest that the treatment of choice of acute porphyric syndromes may be the combination of low doses of heme and zinc-mesoporphyrin or another similarly non-toxic inhibitor of heme oxygenase.
Russo
S M
SM
Department of Medicine, University of Massachusetts Medical Center, Worcester 01655.
Pepe
J A
JA
Cable
E E
EE
Lambrecht
R W
RW
Bonkovsky
H L
HL
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004794:Enzyme Repression; D005290:Ferric Compounds / Q000494:pharmacology; D005984:Glutethimide / Q000494:pharmacology; D006418:Heme / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006537:Heptanoates / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008665:Metalloporphyrins / Q000494:pharmacology*; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011164:Porphyrias / Q000201:enzymology*
D005290:Ferric Compounds; D006537:Heptanoates; D008665:Metalloporphyrins; D006418:Heme; C020804:succinylacetone; C058069:zinc mesoporphyrin; D005984:Glutethimide; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate