Localization of the oxidative defect in phytanic acid degradation in patients with refsum's disease

Mize, Charles E.; Herndon, James H.; Blass, John P.; Milne, G. W. A.; Follansbee, Christopher W.; Laudat, P; Steinberg, Daniel

doi:10.1172/jci106059

Cited by 51 publications

(17 citation statements)

References 30 publications

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“…One cannot exclude the possibility that phytanate may be oxidized relatively more rapidly in vivo than in fibroblast cultures due to contributions of other organ and cell types. However, as reported in the accompanying paper (36), in vivo oxidation of phytanate itself in the three HAP patients studied here was impaired to an extent comparable to that seen in fibroblast cultures.…”

Section: Discussionsupporting

confidence: 80%

“…In those reports and in a companion paper (36), it was shown that HAP patients converted orally administered phytolj'C or intravenously administered phytanic acid-j4C to '4CO2 at much slower rates than did normal controls. Phytanic acid radioactivity also persisted at much higher levels and for longer periods in the patients' plasma than in that of the controls.…”

Section: Discussionmentioning

confidence: 95%

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Refsum's disease: characterization of the enzyme defect in cell culture

Herndon¹,

Steinberg²,

Uhlendorf³

et al. 1969

J. Clin. Invest.

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119

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 95%

Refsum's disease: characterization of the enzyme defect in cell culture

Herndon¹,

Steinberg²,

Uhlendorf³

et al. 1969

J. Clin. Invest.

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119

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“…Like other fatty acids, 70% of the phytanic acid probably exists as triacylglycerol or phospholipid esters that are rapidly oxidized and that vary with dietary conditions (Mohrhauer and Holman, 1963;Mize et al, 1966Mize et al, , 1969. Although the estimated free phytanic acid (2 ,uM) is only at the threshold for RXR io-5 104 stimulation ( Figure 4B), equipotent phytenic acid may also contribute to the RXR effector pool (Allegretto et al, 1993). probably due to cellular toxicity in which, above 64 ,uM, the limits for fatty-acid binding to serum albumin were exceeded (Herndon et al, 1969;Spector et al, 1969).…”

Section: Phytol Metabolites As Transcriptional Signalsmentioning

confidence: 99%

Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR.

Kitareewan

Burka

Tomer

et al. 1996

MBoC

179

135

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RXR is a nuclear receptor that plays a central role in cell signaling by pairing with a host of other receptors. Previously, 9-cis-retinoic acid (9cRA) was defined as a potent RXR activator. Here we describe a unique RXR effector identified from organic extracts of bovine serum by following RXR-dependent transcriptional activity. Structural analyses of material in active fractions pointed to the saturated diterpenoid phytanic acid, which induced RXR-dependent transcription at concentrations between 4 and 64 ,uM. Although 200 times more potent than phytanic acid, 9cRA was undetectable in equivalent amounts of extract and cannot be present at a concentration that could account for the activity. Phytenic acid, another phytol metabolite, was synthesized and stimulated RXR with a potency and efficacy similar to phytanic acid. These metabolites specifically displaced[3H]-9cRA from RXR with Ki values of 4 ,uM, indicating that their transcriptional effects are mediated by direct receptor interactions. Phytol metabolites are compelling candidates for physiological effectors, because their RXR binding affinities and activation potencies match their micromolar circulating concentrations. Given their exclusive dietary origin, these chlorophyll metabolites may represent essential nutrients that coordinate cellular metabolism through RXR-dependent signaling pathways.

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“…In addition, high concentrations of phytanic acid in the plasma of patients with HAP were detected [6][7][8]: whereas normal concentrations of phytanic acid are about 2 /ig/ml plasma, concentrations in the plasma of patients are generally 50-500 times as high. However, three cases have been reported, in which the clinical syndromes are compatible with HAP, but in which no accumulation of phytanic acid either in plasma or in the liver biopsy could be demonstrated [9][10][11], On the other hand, one case has become known in which the concentration of phy tanic acid in the plasma was decidedly elevated without clinical manifesta tions [8],…”

Section: Clinical Manifestationsmentioning

confidence: 99%

Nutritional and Metabolic Aspects of Heredopathia atactica polyneuritiformis (Refsum’s Syndrome)

Lenk¹

1974

Ann Nutr Metab

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In this review on heredopathia atactica polyneuritiformis (Refsum’s syndrome), special emphasis is put on the nutritional and metabolic aspects of the genetically determined disease. In patients afflicted with Refsum’s syndrome, 3,7,11,15-tetramethylhexadecanoic (phytanic) acid is accumulated in the body lipids and in the plasma due to a partial defect in the α-oxidation mechanism. Phytanic acid which is present in the diet itself, is also readily formed in the organism from phytol ubiquitously present in foodstuffs. Biochemical and dietary studies have not yet elucidated whether the neurological symptoms of the disease are caused by high concentrations of phytanic acid or by a deranged metabolism of nerve tissue.

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Localization of the oxidative defect in phytanic acid degradation in patients with refsum's disease

Cited by 51 publications

References 30 publications

Refsum's disease: characterization of the enzyme defect in cell culture

Refsum's disease: characterization of the enzyme defect in cell culture

Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR.

Nutritional and Metabolic Aspects of Heredopathia atactica polyneuritiformis (Refsum’s Syndrome)

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