Tyrosinemia with acute intermittent porphyria: Aminolevulinic acid dehydratase deficiency related to elevated urinary aminolevulinic acid levels

Strife, C. Frederic; Zuroweste, Edward L.; Emmett, Edward A.; Finelli, Vincent N.; Petering, Harold G.; Berry, Helen K.

doi:10.1016/s0022-3476(77)80701-4

Cited by 46 publications

(17 citation statements)

References 24 publications

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“…Some individuals with hereditary tyrosinemia have been reported to display neurological symptoms similar to those observed in patients with AIP (2,3,5,6). The basis of the neurological symptoms in AIP (or in hereditary tyrosinemia) has not been clarified.…”

Section: Discussionmentioning

confidence: 99%

“…These findings indicate that tyrosinemia is a disorder of special pharmacogenetic interest because succinylacetone, an abnormal product of the tyrosine metabolic pathway, INTRODUCTION Hereditary tyrosinemia is an inborn error of tyrosine metabolism transmitted in an autosomal recessive fashion (1). Patients with this disease excrete excessive amounts of urinary 6-aminolevulinic acid (ALA)' (2)(3)(4)(5) and have low ALA dehydratase [EC 4.2.1.24] activity in erythrocytes (6,7) and in liver (7). Acute neurological symptoms resembling those of acute intermittent porphyria (AIP) have also been reported in this disorder (2,3,5,6).…”

mentioning

confidence: 99%

“…Patients with this disease excrete excessive amounts of urinary 6-aminolevulinic acid (ALA)' (2)(3)(4)(5) and have low ALA dehydratase [EC 4.2.1.24] activity in erythrocytes (6,7) and in liver (7). Acute neurological symptoms resembling those of acute intermittent porphyria (AIP) have also been reported in this disorder (2,3,5,6). Low ALA dehydratase activity is thought to result from enzyme inhibition by accumulation of succinylacetone (4,6-dioxoheptanoic acid) in plasma resulting from the deficiency of 4-fumarylacetoacetate hydrolase [EC 3.7.1.2] in this disease (7).…”

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Hereditary Tyrosinemia and the Heme Biosynthetic Pathway. PROFOUND INHIBITION OF δ-AMINOLEVULINIC ACID DEHYDRATASE ACTIVITY BY SUCCINYLACETONE

Sassa¹,

Kappas²

1983

J. Clin. Invest.

132

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A B S T R A C T Succinylacetone (4,6-dioxoheptanoic acid) is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumarylacetoacetate hydrolase. It is known that patients with this hereditary disease excrete excessive amounts of b-aminolevulinic acid (ALA) in urine and that certain patients have an accompanying clinical syndrome resembling that of acute intermittent porphyria (AIP). In order to elucidate the relation of succinylacetone to the heme biosynthetic pathway, we have examined the effects of this metabolite on the cellular heme content of cultured avian hepatocytes and on the activity of purified ALA dehydratase from normal human erythrocytes and from mouse and bovine liver. Our data indicate that succinylacetone is an extremely potent competitive inhibitor of ALA dehydratase in human as well as in animal tissues. By using purified preparations of the enzyme from human erythrocytes and mouse and bovine liver, an inhibitor constant ranging from 2 X 1O-7 M to 3 X 1O-7 M was obtained. In cultured hepatocytes, succinylacetone also inhibited ALA dehydratase activity, decreased the cellular content of heme and cytochrome P-450, and greatly potentiated the induction response of ALA synthase to drugs such as phenobarbital, chemicals such as allylisopropylacetamide and 3,5-dicarbethoxy-1,4-dihydrocollidine, and natural steroids such as etiocholanolone. Four patients with hereditary tyrosinemia have been studied and all were found to have greatly depressed levels of erythrocyte ALA dehydratase activity and elevated concentrations of this inhibitor in urine. These findings indicate that tyrosinemia is a disorder of special pharmacogenetic interest because succinylacetone, an abnormal product of the tyrosine metabolic pathway,

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Hereditary Tyrosinemia and the Heme Biosynthetic Pathway. PROFOUND INHIBITION OF δ-AMINOLEVULINIC ACID DEHYDRATASE ACTIVITY BY SUCCINYLACETONE

Sassa¹,

Kappas²

1983

J. Clin. Invest.

132

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“…A rare cause of aminolaevulinic acid dehydratase inhibition is succinylacetone, a metabolite found in tyrosinaemia (28,29,30 Nomial serum and urine amino acid patterns excluded tyrosinaemia, and therefore the presence of succinylacetone. The failure of dithiothreitol and zinc to restore aminolaevulinic acid dehydratase suggests a primary loss of activity of the enzyme, rather than an Inhibition by lead or succinylacetone.…”

Section: Discussionmentioning

confidence: 99%

Biochemical Diagnosis of an Hereditary Aminolaevulinate Dehydratase Deflciency in a 63-Year-Old Man

Hassoun¹,

Verstraeten²,

Mercelis³

et al. 1989

Clinical Chemistry and Laboratory Medicine

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Summary:Porphyrin metabolism was investigated in a 63-year-old male patient who developed a subacute onset polyneuropathy with predominance of motor signs in the upper limb.The screening for lead, cadmium, mercury, aluminium and thallium was negative. The study of porphyrin metabolism showed remarkable abnormalities, particularly a very high level of plasmatic 5-aminolaevulinic acid contrasting with a normal level of porphobilinogen and a nearly complete loss of activity of aminolaevulinic acid dehydratase with no regenerative response to dithiothreitol or zinc ions. The other causes of aminolaevulinic acid dehydratase deficiency (tyrosinaemia, alcoholism, smoking, cirrhosis, renal insufficiency, diabetes mellitus) were ruled out.The diagnpsis of primary aminolaevulinic acid dehydratase deficiency was proposed and confirmed by the familial study, which revealed the existence of several heterozygous members in this family.

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“…Hypertension is a recognized outcome in HT, even in pediatric subjects (Strife et al, 1977;Gibbs et al, 1993;Klujber et al, 1997;Schlump et al, 2008), and remains an important diagnostic feature of the disease (Bonkovsky, 2005). We hypothesized that the accumulation of SA in type 1 HT may lead to cardiovascular hemoenzyme deficiency, thereby precipitating a hypertensive phenotype.…”

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confidence: 90%

Lack of Hemodynamic Effects After Extended Heme Synthesis Inhibition by Succinylacetone in Rats

Bourque

Benjamin

Adams

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

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Hypertyrosinemia (HT) is a life-threatening condition caused in large part by the buildup of tyrosine metabolites and their derivatives. One such metabolite is succinylacetone (SA), a potent irreversible inhibitor of heme biosynthesis. Heme is a key component of numerous enzymes involved in arterial blood pressure (BP) regulation, including nitric-oxide synthase (NOS) and its downstream mediator soluble guanylyl cyclase (sGC). Because NOS and sGC are important regulators of cardiovascular function, we hypothesized that inhibition of heme supply to these enzymes by SA would result in the induction of a measurable hypertensive response. Male Sprague-Dawley rats were treated with SA (80 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 i.p.) for 14 days, resulting in a marked increase in urinary SA and ␦-aminolevulinic acid (P Ͻ 0.001 for both parameters) and decreased heme concentrations in kidney, liver, spleen, and vascular tissues (P Ͻ 0.05 for all parameters). After SA treatment, systemic nitrite/nitrate excretion was reduced by 72% (P Ͻ 0.001), and renal NOS and sGC activities were decreased by 32 (P Ͻ 0.05) and 38% (P Ͻ 0.01), respectively. SA administration also compromised the ex vivo sensitivity of aorta to endothelium-dependent and -independent vasodilation. Despite these effects, SA treatment failed to induce any changes in BP, as assessed by radiotelemetry. Moreover, BP profiles in the SA-treated animals were less responsive to altered sodium intake. The present results demonstrate that extended inhibition of heme synthesis with SA affects hemoenzyme function, albeit without consequent effects on BP regulation and sodium excretion.

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Tyrosinemia with acute intermittent porphyria: Aminolevulinic acid dehydratase deficiency related to elevated urinary aminolevulinic acid levels

Cited by 46 publications

References 24 publications

Hereditary Tyrosinemia and the Heme Biosynthetic Pathway. PROFOUND INHIBITION OF δ-AMINOLEVULINIC ACID DEHYDRATASE ACTIVITY BY SUCCINYLACETONE

Hereditary Tyrosinemia and the Heme Biosynthetic Pathway. PROFOUND INHIBITION OF δ-AMINOLEVULINIC ACID DEHYDRATASE ACTIVITY BY SUCCINYLACETONE

Biochemical Diagnosis of an Hereditary Aminolaevulinate Dehydratase Deflciency in a 63-Year-Old Man

Lack of Hemodynamic Effects After Extended Heme Synthesis Inhibition by Succinylacetone in Rats

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