Repression of hepatic δ-aminolevulinate synthase by heme and metalloporphyrins: Relationship to inhibition of heme oxygenase

Abstract

Heme- and tin-chelated metalloporphyrins are known to decrease the activity of hepatic δ-aminolevulinate synthase, the rate-controlling enzyme of heme synthesis. We performed experiments in primary chick embryo liver cells with tin-, zinc- and copperchelated porphyrins to assess their effects on activities of δ-aminolevulinate synthase induced by prior treatment of cells with glutethimide and ferric nitrilotriacetate. These different metalloporphyrins were tested to form the experimental foundation for eventual studies in patients with acute porphyrias, in which uncontrolled induction of hepatic δ-aminolevulinate synthase, which plays a key role in pathogenesis of disease. Zinc and tin porphyrins reduced δ-aminolevulinate synthase activities, whereas copperchelated porphyrins did not. When heme (iron protoporphyrin) was added with zinc or tin porphyrins, δ-aminolevulinate synthase activity was further reduced. Effects of the nonheme metalloporphyrins on δ-aminolevulinate synthase were closely correlated with their abilities to inhibit heme oxygenase (r = 0.78). The largest decrease of δ-aminolevulinate synthase (67%) was obtained with zinc mesoporphyrin and heme. Dose-response data indicated that only nanomolar concentrations of zinc mesoporphyrin and heme are required to obtain this effect. We found no effect of exposure to heme (10 μmol/L) or heme (200 nmol/L) plus zinc mesoporphyrin (50 nmol/L) on the half-life of activity of δ-aminolevulinate synthase (1.9 to 2.1 hr, regardless of treatment). This result suggests that the repressive effect of heme is directed toward decreasing synthesis, increasing breakdown or decreasing the translation of the messenger RNA of δ-aminolevulinate synthase. Reduction of δ-aminolevulinate synthase by zinc mesoporphyrin and heme occurred after induction of δ-aminolevulinate synthase by exposure of gliver cells to several chemicals. These results suggest that low doses of zinc mesoporphyrin and heme, in combination, may be a useful treatment for patients with acute porphyria. (HEPATOLOGY 1993;18:119–127).