Differential effects of metalloporphyrins on messenger RNA levels of delta-aminolevulinate synthase and heme oxygenase. Studies in cultured chick embryo liver cells.
The acute porphyrias in relapse are commonly treated with intravenous heme infusion to decrease the activity of delta-aminolevulinic acid synthase, normally the rate-controlling enzyme in heme biosynthesis. The biochemical effects of heme treatment are short-lived, probably due in part to heme-mediated induction of heme oxygenase, the rate-controlling enzyme for heme degradation. In this work, selected nonheme metalloporphyrins were screened for their ability to reduce delta-aminolevulinic acid synthase mRNA and induce heme oxygenase mRNA in chick embryo liver cell cultures. Of the metalloporphyrins tested, only zinc-mesoporphyrin reduced delta-aminolevulinic acid synthase mRNA without increasing heme oxygenase mRNA. The combination of zinc-mesoporphyrin and heme, at nanomolar concentrations, decreased delta-aminolevulinic acid synthase mRNA in a dose-dependent manner. The combination of zinc-mesoporphyrin (50 nM) and heme (200 nM) decreased the half-life of the mRNA for delta-aminolevulinic acid synthase from 5.2 to 2.5 h, while a similar decrease was produced by heme (10 microM) alone (2.2 h). The ability of zinc-mesoporphyrin to supplement the reduction of delta-aminolevulinic acid synthase mRNA by heme, in a process similar to that observed with heme alone, provides a rationale for further investigation of this compound for eventual use as a supplement to heme therapy of the acute porphyrias and perhaps other conditions in which heme may be of benefit.
Cable
E E
EE
Department of Medicine, University of Massachusetts Medical Center, Worcester 01655.
Pepe
J A
JA
Karamitsios
N C
NC
Lambrecht
R W
RW
Bonkovsky
H L
HL
D000624:5-Aminolevulinate Synthetase / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D008099:Liver / Q000196:embryology / Q000201:enzymology*; D008665:Metalloporphyrins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis*
D008665:Metalloporphyrins; D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase