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 activity of hepatic delta-amino-levulinate synthase, the rate-controlling enzyme of heme synthesis. We performed experiments in primary chick embryo liver cells with tin-, zinc- and copper-chelated porphyrins to assess their effects on activities of delta-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 delta-amino-levulinate 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 protoporphyrin) was added with zinc or tin porphyrins, delta-aminolevulinate synthase activity was further reduced. Effects of the nonheme metalloporphyrins on delta-aminolevulinate synthase were closely correlated with their abilities to inhibit heme oxygenase (r = 0.78). The largest decrease of delta-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 mumol/L) or heme (200 nmol/L) plus zinc mesoporphyrin (50 nmol/L) on the half-life of activity of delta-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 delta-aminolevulinate synthase.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Biochemistry and Molecular Biology, University of Massachusetts Medical Center, Worcester 01655.
Cable
J W
JW
Bonkovsky
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HL
D000624:5-Aminolevulinate Synthetase / Q000037:antagonists & inhibitors*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D003300:Copper; D005984:Glutethimide / Q000494:pharmacology; D006418:Heme / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D007501:Iron / Q000494:pharmacology; D008099:Liver / Q000196:embryology / Q000201:enzymology*; D008665:Metalloporphyrins / Q000494:pharmacology*; D014001:Tin; D015032:Zinc
D008665:Metalloporphyrins; D006418:Heme; D014001:Tin; D003300:Copper; C058069:zinc mesoporphyrin; D005984:Glutethimide; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; D015032:Zinc