HEPATIC 5-AMINOLEVULINIC ACID SYNTHASE MESSENGER-RNA STABILITY IS MODULATED BY INHIBITORS OF HEME-BIOSYNTHESIS AND BY METALLOPORPHYRINS

Hepatic 5-aminolevulinic acid synthase, the first and normally rate-co ntrolling enzyme of heme biosynthesis, is regulated by heme. One of th e known mechanisms whereby increased cellular heme regulates 5-aminole vulinic acid synthase is by decreasing the stability of its mRNA. In p rimary cultures of chick embryo liver cells, we tested whether a decre ase in cellular heme might increase 5-aminolevulinic acid synthase mRN A stability and whether heme or other metalloporphyrins could reverse this stabilization. We found that: (a) The stability of 5-aminolevulin ic acid synthase mRNA was markedly increased by inhibitors of heme bio synthesis, namely, 4,6-dioxoheptanoic acid or deferoxamine; (b) This i ncreased stability of 5-aminolevulinic acid synthase mRNA was reversed by the addition of heme (10 mu M) or by the combination of zinc mesop orphyrin (50 nM), an inhibitor of heme oxygenase, and heme (200 nM); ( c) Repression of 5-aminolevulinic acid synthase mRNA levels by zinc me soporphyrin (10 mu M) was due to inhibition of heme oxygenase, rather than a direct, heme-like, effect of zinc mesoporphyrin on 5-aminolevul inic acid synthase mRNA; (d) Among the several non-heme metalloporphyr ins tested, only zinc mesoporphyrin and chromium mesoporphyrin signifi cantly decreased 5-aminolevulinic acid synthase mRNA without increasin g heme oxygenase mRNA.