Acute Intermittent Porphyria: The First “Overproduction Disease” Localized to a Specific Enzyme

Tschudy, Donald P.; Perlroth, Mark G.; Marver, Harvey S.; Collins, Annie; Hunter, George W.; Rechcigl, Miloslav

doi:10.1073/pnas.53.4.841

Cited by 166 publications

(46 citation statements)

References 20 publications

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“…That this mechanism is plausible is supported by the recent demonstration that experimentally produced partial defects in heme synthesis in cultured hepatocytes results in increased ALA-synthetase activity and increased ALA-svnthetase induction by 2-allyl-2-isopropylacetamide (37). Although this speculative mechanism is attractive, other possibilities exist (1,7,12,34).…”

Section: Resultsmentioning

confidence: 99%

“…On the basis of clinical features alnd a unique pattern of excessive excretion of porphyrins and porphyrin precursors, IAP has been distinguished from two related genetic hepatic porphyrias, variegate porphyria and hereditary coproporphyria. In all three of these porphyrias the liver is the primary site of overproduction of porphyrin precursors as a consequence of increased activity of 8-aminolevulinic acid synthetase (ALA-synthetase) (1)(2)(3)(4)(5)(6)(7)(8), the first and rate-limiting enzyme in heme biosynthesis (9)(10)(11). TAP is also associated with (lecreased hepatic uroporphyrinogen I synthetase (URO-Isynthetase) activity in contrast to variegate porphyria (7,12).…”

Section: Introductionmentioning

confidence: 99%

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Decreased Red Cell Uroporphyrinogen I Synthetase Activity in Intermittent Acute Porphyria

Strand¹,

Meyer²,

Felsher³

et al. 1972

J. Clin. Invest.

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132

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Decreased Red Cell Uroporphyrinogen I Synthetase Activity in Intermittent Acute Porphyria

Strand¹,

Meyer²,

Felsher³

et al. 1972

J. Clin. Invest.

Self Cite

132

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“…As discussed earlier, several observations suggest that the excessive protoporphyrin produced in this disease does not originate solely from the erythroid cells, but probably is derived also from other sources. Among these the liver is a prime suspect because (a) it is a site of very active porphyrin and heme biosynthesis (27,28), (b) it is the principal site of porphyrin overproduction in several other types of porphyria (29,30), and (c) in EPP there is a reciprocal relationship between caloric intake and porphyrin excretion, an effect which may be explained by carbohydrate mediated suppression of hepatic porphyrin production (12). The present results will be analyzed in terms of two extreme models, the first of which assumes that all excess protoporphyrin is derived from the erythroid cells, and the second, that the liver is the sole source of the protoporphyrin.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietic protoporphyria: evidence for multiple sites of excess protoporphyrin formation

Scholnick¹,

Marver²,

Schmid³

1971

J. Clin. Invest.

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“…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 negative feedback induction of ALA-synthetase (2)(3)(4)(5)(6). In production of the acute attack, this is usually augmented by an exogenous factor.…”

mentioning

confidence: 96%

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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Acute Intermittent Porphyria: The First “Overproduction Disease” Localized to a Specific Enzyme

Cited by 166 publications

References 20 publications

Decreased Red Cell Uroporphyrinogen I Synthetase Activity in Intermittent Acute Porphyria

Decreased Red Cell Uroporphyrinogen I Synthetase Activity in Intermittent Acute Porphyria

Erythropoietic protoporphyria: evidence for multiple sites of excess protoporphyrin formation

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

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