Repression of the Overproduction of Porphyrin Precursors in Acute Intermittent Porphyria by Intravenous Infusions of Hematin

Bonkowsky, Herbert L.; Tschudy, Donald P.; Collins, Annie; Doherty, Joyce M.; Bossenmaier, Irene; Cardinal, Ruth; Watson, C. J.

doi:10.1073/pnas.68.11.2725

Cited by 181 publications

(82 citation statements)

References 26 publications

(26 reference statements)

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“…85 Herbert Bonkovsky and his colleagues at the National Institutes of Health, under the direction of Cecil Watson, treated a woman with endstage acute intermittent porphyria with intravenous hematin and showed conclusively a profound suppression of porphyrin precursors, porphobilinogen and ALA, which were grossly elevated before therapy. 86 This result confirmed indirectly in vivo the feedback inhibition of ALA synthase by heme. The patient did not survive but the data served as proof of principle that led to the introduction of lyophilized hematin in the United States and heme arginate in Europe and other parts of the world, for patients who fail standard therapy with intravenous glucose or when the attacks are severe.…”

supporting

confidence: 76%

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Mbbs

2006

Hepatology

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supporting

confidence: 76%

Seeing purple†

Mbbs

2006

Hepatology

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“…administration of hemin, which provides exogenous heme for the negative feedback inhibition of ALAS1, thereby decreasing ALA and PBG production (11)(12)(13). Although patients generally respond well, its effect is slow, typically requiring three to four daily infusions to normalize the elevated plasma and urinary ALA and PBG concentrations (14).…”

mentioning

confidence: 99%

RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice

Yasuda

Gan

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. Here, we describe preclinical studies of liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) in a mouse model of acute intermittent porphyria, the most common acute hepatic porphyria. A single i.v. dose of Alas1-siRNA prevented the phenobarbital-induced biochemical acute attacks for approximately 2 wk. Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic porphyrias.RNAi therapeutics | liver-targeted siRNA | heme biosynthetic disorders T he acute hepatic porphyrias are caused by the deficient activities of specific enzymes in the heme biosynthetic pathway and include three autosomal dominant diseases-acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP)-and the autosomal recessive 5-aminolevulinic acid dehydratase deficiency porphyria (ADP) (1). These inherited metabolic disorders are characterized by lifethreatening acute neurovisceral attacks that include severe abdominal pain, hypertension, tachycardia, constipation, motor weakness, seizures, and paralysis (1). Various factors, including cytochrome P450 (CYP)-inducing drugs, dieting, and hormonal changes precipitate the acute attacks by increasing the expression of hepatic 5-aminolevulinic acid synthase (ALAS1), the first and rate-limiting enzyme of the heme biosynthetic pathway (2-6). When hepatic ALAS1 is induced, the respective enzyme deficiencies create a metabolic bottleneck, thereby decreasing hepatic heme production and depleting the "free" heme pool. This leads to the loss of the negative feedback inhibition of heme on ALAS1 (7-9) and, consequently, further up-regulation of hepatic ALAS1 expression. As hydroxymethylbilane synthase (HMBS)-the third enzyme in the heme biosynthetic pathway-is less abundant in comparison with the other heme biosynthetic enzymes (10), it becomes rate-limiting when ALAS1 is markedly increased. As a result, the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) are overproduced in the liver and are markedly accumulated in the plasma and urine during the acute attacks (only ALA accumulates ...

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“…The repressive or inhibitory feedback effect of heme on ALA-synthetase induction (5, 6) led to a trial, by Bonkowsky et al (10), of hematin infusions in AIP. The subject also suffered from "malignant" primary hypertension with renal insufficiency and uremia leading to early demise, but probably unrelated in any direct fashion to the porphyric relapse.…”

mentioning

confidence: 99%

Postulated deficiency of hepatic heme and repair by hematin infusions in the "inducible" hepatic porphyrias.

Watson¹,

Pierach²,

Bossenmaier³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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There is compelling, indirect evidence of hepatic heme deficiency due primarily to the respective genetic errors of the three inducible hepatic porphyrias, acute intermittent porphyria, porphyria variegata, and hereditary copropor hyria. The induction is enhanced by exogenous inducers such as barbiturate, estrogens, and other "porphyrogenic" chemicals and factors, including glucose deprivation. The newer knowledge of the induction of 6-aminolevulinic acid synthetase [6-aminolevulinate synthase; succinyl-CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37] in relation to inadequate heme, and repression by heme, stimulated early trials of hematin infusions to overcome the acute relapse in the foregoing inducible porphyrias. Recently this experience has been considerably expanded, 143 infusions of hematin having been given in 22 cases. Studies of the effect on the serum concentrations of 6-aminolevulinic acid and porphobilinogen have shown a highly significant decline, often to 0, especially of 6-aminolevulinic acid. A distinct relationship to the clinical severity of the attack has been evident in the frequency and magnitude of decline of serum 5-aminolevulinic acid and porphobilinogen. This was regularly associated with objective clinical improvement. The present preliminary report will consider briefly some basic and associated clinical aspects of the remission due to hematin, in cases of "inducible" hepatic porphyria. In a later paper this effect will be considered in greater detail (1).Those forms of hepatic porphyria in which various inducing factors are liable to precipitate a life-threatening acute neurologic relapse are appropriately grouped under the term inducible (1). This relates to 3-aminolevulinic acid synthetase [ALA-synthetase; 5-aminolevulinate synthase; succinyl-CoA: glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37], the rate-limiting enzyme of porphyrin and heme biosynthesis (2-6). The term inducible embraces the three autosomal dominant genetic errors, acute intermittent porphyria (AIP), porphyria variegata (PV), and hereditary hepatic coproporphyria (HC), but it does not include hepatic porphyria cutanea tarda, in which evidence of induction is slight or lacking (7, 8), as well as the neurologic symptoms of the acute attack in the inducible forms and the prominent excesses of porphyrin precursors, ALA and porphobilinogen (PBG) in liver, urine, and blood serum, increases of which are usually observed at least in the early symptomatic stage of the porphyric relapse. The inducible forms are characterized by derepression or impaired feedback regulation and secondary induction of hepatic ALA-synthetase (6) (see above). There is reason to believe that this is related to hepatic heme deficiency incident to the respective genetic (partial) lack of uroporphyrinogen synthetase in AIP (6), heme synthetase in PV (7), and coproporphyrinogenase in HC (9). Any one of these traits constitutes a partial block in heme synthesis, responsible, as already mentioned, for the negati...

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Repression of the Overproduction of Porphyrin Precursors in Acute Intermittent Porphyria by Intravenous Infusions of Hematin

Cited by 181 publications

References 26 publications

Seeing purple†

Seeing purple†

RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice

Postulated deficiency of hepatic heme and repair by hematin infusions in the "inducible" hepatic porphyrias.

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