REPRESSION OF HEPATIC DELTA-AMINOLEVULINATE SYNTHASE BY HEME AND METALLOPORPHYRINS - RELATIONSHIP TO INHIBITION OF HEME OXYGENASE

Heme- and tin-chelated metalloporphyrins are known to decrease the act ivity of hepatic delta-aminolevulinate synthase, the rate-controlling enzyme of heme synthesis. We performed experiments in primary chick em bryo liver cells with tin-, zinc- and copper-chelated porphyrins to as sess their effects on activities of delta-aminolevulinate synthase ind uced by prior treatment of cells with glutethimide and ferric nitrilot riacetate. These different metalloporphyrins were tested to form the e xperimental foundation for eventual studies in patients with acute por phyrias, in which uncontrolled induction of hepatic delta-aminolevulin ate synthase, which plays a key role in pathogenesis of disease. Zinc and tin porphyrins reduced delta-aminolevulinate synthase activities, whereas copper-chelated porphyrins did not. When heme (iron protoporph yrin) was added with zinc or tin porphyrins, delta-aminolevulinate syn thase activity was further reduced. Effects of the nonheme metalloporp hyrins on delta-aminolevulinate synthase were closely correlated with their abilities to inhibit heme oxygenase (r = 0.78). The largest decr ease of delta-aminolevulinate synthase (67%) was obtained with zinc me soporphyrin and heme. Dose-response data indicated that only nanomolar concentrations of zine mesoporphyrin and heme are required to obtain this effect. We found no effect of exposure to heme (10 mumol/L) or he me (200 nmol/L) plus zinc mesoporphyrin (50 nmol/L) on the half-life o f activity of delta-aminolevulinate synthase (1.9 to 2.1 hr, regardles s of treatment). This result suggests that the repressive effect of he me is directed toward decreasing synthesis, increasing breakdown or de creasing the translation of the messenger RNA of delta-aminolevulinate synthase. Reduction of delta-aminolevulinate synthase by zine mesopor phyrin and heme occurred after induction of delta-aminolevulinate synt hase by exposure of liver cells to several chemicals. These results su ggest that low doses of zinc mesoporphyrin and heme, in combination, m ay be a useful treatment for patients with acute porphyria.