The Role of Iron in the Pathogenesis of Porphyria Cutanea Tarda

Kushner, James P.; Lee, G B; Nacht, Sergio

doi:10.1172/jci107131

Cited by 70 publications

(26 citation statements)

References 29 publications

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“…However, the pattern of (6)(7)(8)(9), and a previous report from our laboratory demonstrated that ferrous ion was a potent inhibitor of hepatic COSYN activity (10). The present report describes the inhibitory effect of ferrous ion on hepatic URODE-CARB activity.…”

Section: Introductionmentioning

confidence: 48%

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The role of iron in the pathogenesis of porphyria cutanea tarda. II. Inhibition of uroporphyrinogen decarboxylase.

Kushner¹,

Steinmüller²,

Lee³

1975

J. Clin. Invest.

127

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A B S T R A C T Porphyria cutanea tarda is characterized biochemically by excessive hepatic synthesis and urinary excretion of uroporphyrin I and 7-carboxyl porphyrins. This pattern of excretion suggests an impaired ability to decarboxylate uroporphyrinogen to the 4-carboxyl porphyrinogen, coproporphyrinogen, a reaction catalyzed by the enzyme uroporphyrinogen de-carboxylase.Because clinical evidence has implicated iron in the pathogenesis of porphyria cutanea tarda, these experiments were designed to study the effect of iron on uroporphyrinogen decarboxylase in porcine crude liver extracts.Mitochondria-free crude liver extracts were preincubated with ferrous ion and aliquots were assayed for uroporphyrinogen decarboxylase activity. Uroporphyrinogens I and III, the substrates for the decarboxylase assay, were prepared enzymatically from [3H]porphobilinogen. The products of the decarboxylase reaction were identified and quantitated by three methods: (a) extraction into ethyl acetate at pH 4.0, back extraction into 1.5 N HCO and spectrophotometric quantitation; (b) adsorption onto talc, esterification, paper chromatographic identification, and quantitation by liquid scintillation counting; and (c) adsorption onto talc, esterification, thin-layer chromatographic identification on silica gel, and quantitation by liquid scintillation counting. The thin-layer scintillation method proved most sensitive as it was the only method which accurately identified and quantitated the 7-carboxyl porphyrin reaction product. Uroporphyrinogens I and III were decarboxylated at the same rate by porcine hepatic uroporphyrinogen decarboxylase, and the addition of iron induced marked inhibition of the decarboxylase activity. Orthophenanthroline blocked the inhibitory effect of iron.The inhibition of uroporphyrinogen decarboxylase by ferrous ion, coupled with its previously reported inhibitory effect on uroporphyrinogen III cosynthetase, provides a possible biochemical explanation for the pattern of urinary porphyrin excretion observed in patients with porphyria cutanea tarda and the clinical association with disordered iron metabolism.

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Section: Introductionmentioning

confidence: 48%

“…In a previous report in which porphyrin synthesis in mitochoncria-free crude liver extracts was studied, it was noted that the synthesis of COPRO was gradually inhibited by increasing concentrations of ferrous ion (10). Maximal inhibition occurred at iron concentrations of 0.08-0.3 mM.…”

Section: Resultsmentioning

confidence: 94%

The role of iron in the pathogenesis of porphyria cutanea tarda. II. Inhibition of uroporphyrinogen decarboxylase.

Kushner¹,

Steinmüller²,

Lee³

1975

J. Clin. Invest.

127

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“…An increase in the synthesis of uroporphyrinogen despite normal ALA synthetase activity suggests a regulatory mechanism later in the heme biosynthetic pathway. We previously reported that, under conditions which inhibit both URODECARB and uroporphyrinogen III cosynthetase (heating or the addition of ferrous iron) uroporphyrin synthesis from porphobilinogen in crude liver extracts was greatly increased (17). These studies suggest a regulatory effect on uroporphyrinogen I synthetase activity by URODECARB and(or) uroporphyrinogen III cosynthetase.…”

Section: Introductionmentioning

confidence: 91%

“…alters hepatic porphyrin metabolism in a way that parallels the abnormalities observed in PCT (17). However, the vast majority of patients with alcoholic liver disease and hepatic siderosis do not develop PCT. This clinical observation has led to speculation that patients with PCT have an occult genetic abnormality expressed only when the liver cell is injured in a specific way (18).…”

Section: Introductionmentioning

confidence: 96%

An inherited enzymatic defect in porphyria cutanea tarda: decreased uroporphyrinogen decarboxylase activity.

Kushner¹,

Barbuto²,

Lee³

1976

J. Clin. Invest.

269

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A B S T R A C T Uroporphyrinogen decarboxylaseWith the erythrocyte assay, multiple examples of decreased uroporphyrinogen decarboxylase activity were detected in members of three families of patients with porphyria cutanea tarda. In two of these families subclinical porphyria was also recognized. The inheritance pattern was consistant with an autosomal dominant trait.The difference in erythrocyte enzymatic activity between men and women was not explained but could have been due to estrogens. This possibility was supported by the observation that men under therapy with estrogens for carcinoma of the prostate had values in the normal female range.

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“…Recent studies synthase. 51 However, this effect was only produced in vitro suggest that the ratio of transferrin receptor/serum ferritin in the presence of rather high and nonphysiological concenprovides the best estimate of the iron status of a healthy trations of iron and has not been confirmed by further studpopulation and is the most reliable parameter for distinguish-ies. Thus, its clinical importance or physiological occurrence ing iron deficiency anemia from the anemia of chronic dis-is far from established.…”

Section: 13mentioning

confidence: 97%

An update on iron metabolism: Summary of the Fifth International Conference on Disorders of Iron Metabolism

Bonkovsky¹

1996

Hepatology

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The Role of Iron in the Pathogenesis of Porphyria Cutanea Tarda

Abstract: A B S T R A C T Porphyria cutanea tarda (PCT

Cited by 70 publications

References 29 publications

The role of iron in the pathogenesis of porphyria cutanea tarda. II. Inhibition of uroporphyrinogen decarboxylase.

The role of iron in the pathogenesis of porphyria cutanea tarda. II. Inhibition of uroporphyrinogen decarboxylase.

An inherited enzymatic defect in porphyria cutanea tarda: decreased uroporphyrinogen decarboxylase activity.

An update on iron metabolism: Summary of the Fifth International Conference on Disorders of Iron Metabolism

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