The effects of metalloporphyrins, porphyrins and metals on the activity of delta-aminolevulinic acid synthase in monolayers of chick embryo liver cells

Schoenfeld, Nili; Wysenbeek, A J; Greenblat, Yehudit; Epstein, O; Atsmon, A; Tschudy, Donald P.

doi:10.1016/0006-2952(84)90696-8

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…The kinetics of the conversion of ALA to heme in human liver resembles that of chicks more closely than that of rats (38,39). Heme-albumin solutions have been effective in cultured cells and humans at reducing ALA synthase activity (9,12,30,36) and excretions of ALA and PBG (1-3, 5-8, 40). We have used the chick embryo liver culture system to test various MePn-albumin complexes for effects on heme metabolism (30,41).…”

Section: Introductionmentioning

confidence: 99%

“…Heme reduces hepatic ALA synthase levels in various experimental models of acute porphyria (9)(10)(11)(12) and apparently has the same effect in patients suffering from acute porphyria (5)(6)(7)(8). The mechanism(s) whereby heme exerts a repressive effect on hepatic ALA synthase may be manifold, including decreasing mRNA stability (13,14) and decreasing import of the enzyme into mitochondria (15,16).…”

Section: Introductionmentioning

confidence: 99%

“…Primary chick embryo liver cell cultures are a simple, reproducible system for studying hepatic porphyrin metabolism and its regulation (9,12,15,30,(34)(35)(36)(37). The kinetics of the conversion of ALA to heme in human liver resembles that of chicks more closely than that of rats (38,39).…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of metalloporphyrins on messenger RNA levels of delta-aminolevulinate synthase and heme oxygenase. Studies in cultured chick embryo liver cells.

Cable¹,

Pepe²,

Karamitsios³

et al. 1994

J. Clin. Invest.

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The acute porphyrias in relapse are commonly treated with intravenous heme infusion to decrease the activity of 6-aminolevulinic acid synthase, normally the rate-controlling enzyme in heme biosynthesis. The biochemical effects of heme treatment are short-lived, probably due in part to heme-mediated induction of heme oxygenase, the rate-controlling enzyme for heme degradation. In this work, selected nonheme metalloporphyrins were screened for their ability to reduce 6-aminolevulinic acid synthase mRNA and induce heme oxygenase mRNA in chick embryo liver cell cultures. Of the metalloporphyrins tested, only zinc-mesoporphyrin reduced 8-aminolevulinic acid synthase mRNA without increasing heme oxygenase mRNA. The combination of zincmesoporphyrin and heme, at nanomolar concentrations, decreased 8-aminolevulinic acid synthase mRNA in a dosedependent manner. The combination of zinc-mesoporphyrin (50 nM) and heme (200 nM) decreased the half-life of the mRNA for 6-aminolevulinic acid synthase from 5.2 to 2.5

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential effects of metalloporphyrins on messenger RNA levels of delta-aminolevulinate synthase and heme oxygenase. Studies in cultured chick embryo liver cells.

Cable¹,

Pepe²,

Karamitsios³

et al. 1994

J. Clin. Invest.

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“…The treatment of choice for all but the mildest attacks of acute porphyria is intravenous heme (11)(12)(13)(14)(15), first described 22 yr ago (15). Heme reduces hepatic ALA synthase levels in various experimental models of acute porphyria (16)(17)(18)(19) and undoubtedly has the same effect in patients with acute porphyria (11)(12)(13)(14)(15).…”

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confidence: 99%

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

Cable

Bonkovsky

1993

Hepatology

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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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“…For example, CoPPIX has been shown to inhibit the rate-limiting heme synthesis enzyme δ-aminolevulenic acid synthase (Schoenfeld, et al, 1984). The combination of heme synthesis inhibition and degradation (the latter from induction of HO-1) causes a reduction of cytochrome P-450 in the liver (Drummond and Kappas, 1982).…”

Section: Discussionmentioning

confidence: 99%

Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency

Barr

Weitz

Atkin

et al. 2015

Chemistry & Biology

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SUMMARY Processing of microRNA primary transcripts (pri-miRNAs) is highly regulated and defects in the processing machinery play a key role in many human diseases. In 22q11.2 deletion syndrome (22q11.2DS), heterozygous deletion of DiGeorge critical region gene 8 (DGCR8) causes a processing deficiency, which contributes to abnormal brain development. The DGCR8 protein is the RNA-binding partner of Drosha ribonuclease, both essential for processing canonical pri-miRNAs. To identify an agent that can compensate reduced DGCR8 expression, we screened for metalloporphyrins that can mimic the natural DGCR8 heme cofactor. We found that Co(III) protoporphyrin IX (PPIX) stably binds DGCR8 and activates it for pri-miRNA processing in vitro and in HeLa cells. Importantly, treating cultured Dgcr8+/− mouse neurons with Co(III)PPIX can compensate the pri-miRNA processing defects. Co(III)PPIX is effective at concentrations as low as 0.2 μM and is not degraded by heme degradation enzymes, making it useful as a research tool and a potential therapeutic.

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The effects of metalloporphyrins, porphyrins and metals on the activity of delta-aminolevulinic acid synthase in monolayers of chick embryo liver cells

Cited by 11 publications

References 27 publications

Differential effects of metalloporphyrins on messenger RNA levels of delta-aminolevulinate synthase and heme oxygenase. Studies in cultured chick embryo liver cells.

Differential effects of metalloporphyrins on messenger RNA levels of delta-aminolevulinate synthase and heme oxygenase. Studies in cultured chick embryo liver cells.

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

Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency

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