DIFFERENTIAL-EFFECTS OF METALLOPORPHYRINS ON MESSENGER-RNA LEVELS OF DELTA-AMINOLEVULINATE SYNTHASE AND HEME OXYGENASE

The acute porphyrias in relapse are-commonly treated with intravenous heme infusion to decrease the activity of delta-aminolevurinic acid sy nthase, normally the rate-controlling enzyme in heme biosynthesis. The biochemical effects of heme treatment are short-lived, probably due i n part to heme-mediated induction of heme oxygenase, the rate-controll ing enzyme for heme degradation. In this work, selected nonheme metall oporphyrins were screened for their ability to reduce delta-aminolevul inic acid synthase mRNA and induce heme oxygenase mRNA in chick embryo liver cell cultures. Of the metalloporphyrins tested, only zinc-mesop orphyrin reduced delta-aminolevulinic acid synthase mRNA without incre asing heme oxygenase mRNA. The combination of zinc-mesoporphyrin and h eme, at nanomolar concentrations, decreased delta-aminolevulinic acid synthase mRNA in a dose-dependent manner. The combination of zinc-meso porphyrin (50 nM) and heme (200 nM) decreased the half-life of the mRN A for delta-aminolevulinic acid synthase from 5.2 to 2.5 h, while a si milar decrease was produced by heme (10 mu M) alone (2.2 h). The abili ty of zinc-mesoporphyrin to supplement the reduction of delta-aminolev ulinic acid synthase mRNA by heme, in a process similar to that observ ed 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.