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 porphyria s that recapitulates the biochemical features of the human syndrome. I n chick embryo liver cells in primary culture exposed to glutethimide and 4,6-dioxoheptanoic acid, heme alone produced a transient dose-depe ndent decrease in delta-aminolevulinate synthase and a concomitant inc rease in heme oxygenase. The addition of low concentrations of zinc-me soporphyrin (50-200 nM), an inhibitor of heme oxygenase, led to more p rolonged decreases in activity of the synthase and to an additive effe ct with heme. These effects of zinc-mesoporphyrin were associated with prolonged inhibition of heme oxygenase. These results suggest that th e treatment of choice of acute porphyric syndromes may be the combinat ion of low doses of heme and zinc-mesoporphyrin or another similarly n on-toxic inhibitor of heme oxygenase.