The Effects of Haem Arginate and Haematin upon the Allylisopropylacetamide Induced Experimental Porphyria in Rats

Tokola, Olavi; Lindén, Inge‐Britt; Tenhunen, Raimo

doi:10.1111/j.1600-0773.1987.tb01778.x

Cited by 14 publications

(7 citation statements)

References 15 publications

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“…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%

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%

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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“…A few metalloporphyrins including heme arginate have previously been studied in neonatal and adult rats af-ter IP administration, but no data on bioavailability were reported. 12,21,29,30 For mice the LD50 of intravenous, oral, and IP heme arginate has been determined. 29 For comparison of the efficacy of the 2 compounds studied, intravenous administration would be desirable, but this was not possible for practical reasons.…”

Section: Discussionmentioning

confidence: 99%

“…The effects of subcutaneous Sn protoporphyrin and intraperitoneal (IP) heme arginate have been studied in allylisopropyl acetamide-treated rats. [28][29][30] A mouse model of hepatic porphyria has been generated by targeted disruption of the porphobilinogen deaminase (PBGD) gene in this laboratory. 2,3,31 This animal model has reduced PBGD activity and mimics the biochemical situation of a porphyric attack when treated with phenobarbital (Pheno), i.e., massively increased ALAS in the liver and excessive levels of ALA in blood and urine.…”

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confidence: 99%

Zinc mesoporphyrin represses induced hepatic 5-aminolevulinic acid synthase and reduces heme oxygenase activity in a mouse model of acute hepatic porphyria

et al. 2001

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Zinc mesoporphyrin (ZnMP) is a potent inhibitor of heme oxygenase (HO) and represses 5-aminolevulinic acid synthase (ALAS). These properties make it a potential candidate for treatment of inducible acute hepatic porphyrias, diseases characterized by neurovisceral symptoms, and massive ALAS induction. Effects of intraperitoneal ZnMP (2.5-10 mol/kg/d) and heme arginate (3-6 mg/kg/d) on plasma levels of 5-aminolevulinic acid (ALA), on messenger RNA (mRNA), and activity of hepatic ALAS and HO were studied in porphobilinogen deaminase-deficient mice treated with phenobarbital (100 mg/kg/d) to induce ALAS. ZnMP (5 mol/kg/d) led to a significant reduction of plasma ALA levels to 31% of controls (P < .01) by lowering the activity of hepatic mitochondrial and cytosolic ALAS to 29% and 25% of controls, respectively (P < .03). ZnMP decreased the mRNA levels of hepatic ALAS to 53% (P < .03) of controls and this repression was more pronounced than that achieved with heme arginate. In contrast to heme arginate, ZnMP led to a significant reduction of HO activity. We conclude that the combined effect of ZnMP on highly induced ALAS and on HO may be of potential benefit for human acute hepatic porphyrias and therefore merits further in vivo investigations addressing questions raised by this study. (HEPATOLOGY 2001;33:1217-1222

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“…The effect of drugs on porphyrin biosynthesis can be examined in various experimental models of porphyria. In vivo rat models have been used for testing of drugs and anaesthetics Tokola et al 1987;Böhrer et al 1995;Goerz et al 1997). Alternatively, the widely used chick hepatocyte culture system, utilising chick embryo hepatocytes pretreated with desferrioxamine, is capable of detecting many porphyrogenic drugs.…”

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confidence: 99%

Effect of Tiagabine and Topiramate on Porphyrin Metabolism in an in vivo Model of Porphyria

2001

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Administration of many antiepileptic drugs to patients with porphyria can precipitate an acute porphyric crisis. Information on the porphyrogenic activity of new antiepileptic drugs is still limited. In the presented study, the effects of tiagabine and topiramate on porphyrin metabolism were evaluated in an in vivo model of porphyria. Administration of the protoporphyrinogen oxidase inhibitor oxadiazon (12.5 mg/kg/day) for four days to male Wistar rats caused a partial block of porphyrin biosynthesis, thus mimicking the condition of quiescent variegate porphyria. Administration of phenobarbital (75 mg/kg/day) to oxadiazon-pretreated rats increased liver porphyrin content, liver porphobilinogen content (means 480 nmol/g, control less than 20 nmol/g) and urinary excretion of porphobilinogen (means 1,000 micromol/l, control less than 20 micromol/l). Tiagabine (75 mg/kg/day) and topiramate (75 mg/kg/day) increased liver porphobilinogen content (means 33 and 53 nmol/g respectively) and urinary porphobilinogen concentration (240 and 490 micromol/l respectively). Similar results were obtained in oxadiazon-treated BALB/c mice. In untreated rats, tiagabine and topiramate caused a moderate increase of hepatic pentoxyresorufin-O-dealkylase activity (approximately 100 and 200 pmol/min./mg respectively, controls 15 pmol/min./mg). These data demonstrate that administration of tiagabine or topiramate to oxadiazon-treated animals can provoke a condition resembling an acute porphyric attack and suggest that administration of these drugs to patients with suspected porphyria should be avoided. However, 5-day administration of both tiagabine and topiramate (75 mg/kg) is considerably less porphyrogenic than phenobarbital administered at the same dose.

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The Effects of Haem Arginate and Haematin upon the Allylisopropylacetamide Induced Experimental Porphyria in Rats

Cited by 14 publications

References 15 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.

Zinc mesoporphyrin represses induced hepatic 5-aminolevulinic acid synthase and reduces heme oxygenase activity in a mouse model of acute hepatic porphyria

Effect of Tiagabine and Topiramate on Porphyrin Metabolism in an in vivo Model of Porphyria

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