Metabolism of Phytanic Acid in Refsum's Disease

Billimoria, J. D.; Gibberd, F. B.; Clemens, Marcell; Whitelaw, M. N.

doi:10.1016/s0140-6736(82)90760-7

Cited by 23 publications

(7 citation statements)

References 9 publications

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“…Earlier studies have provided evidence suggesting that phytanic acid does undergo x-oxidation under in vivo conditions [9][10][11]. More recently we have shown that the first step of the x-oxidation pathway, i.e.…”

Section: Introductionmentioning

confidence: 83%

Identification of the cytochrome P450 enzymes responsible for the ω‐hydroxylation of phytanic acid

Komen

Wanders

2006

FEBS Letters

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Patients suffering from Refsum disease have a defect in the a-oxidation pathway which results in the accumulation of phytanic acid in plasma and tissues. Our previous studies have shown that phytanic acid is also a substrate for the x-oxidation pathway. With the use of specific inhibitors we now show that members of the cytochrome P450 (CYP450) family 4 class are responsible for phytanic acid x-hydroxylation. Incubations with microsomes containing human recombinant CYP450s (Supersomes TM ) revealed that multiple CYP450 enzymes of the family 4 class are able to x-hydroxylate phytanic acid with the following order of efficiency: CYP4F3A > CYP4F3B > CYP4F2 > CYP4A11.

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Section: Introductionmentioning

confidence: 83%

Identification of the cytochrome P450 enzymes responsible for the ω‐hydroxylation of phytanic acid

Komen

Wanders

2006

FEBS Letters

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“…The intake of PA for human adults is estimated to be about lmg/kg/day, but probably varies widely (Steinberg et al (Billimoria et al 1982). It seems advisable for patients with this disease to have as low levels as possible, and we aimed at under 1 Omg/ 1 OOml .…”

Section: Discussionmentioning

confidence: 99%

A Child with Refsum's Disease: Successful Treatment with Diet and Plasma Exchange

Dickson

Mortimer²,

Faed³

et al. 1989

Develop Med Child Neuro

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SUMMARY A child with Refsum's disease presented with cardiac failure, marked muscle wasting, weakness and inco‐ordination. Management with multiple plasma exchanges and dietary restriction of phytanic acid intake has reversed the disabling features of the disease, although levels still remain higher than target values. Low phytanic acid intake is being achieved by restriction of total fat to 10 to 12g/day, while allowing free amounts of fruit and green vegetables. RÉSUMÉ Un enfant atteint de maladie de Refsum: traitement efficace par régime et échange de plasma Une insuffisance cardiaque, une atrophie musculaire accentuée avec faiblesse et incoordination ont été constatées chez un enfant présentant une maladie de Refsum. Le traitement par échanges plasmatiques répétés et restriction diététique d'absorption d'acide phytanique fit régresser les manifestations incapacitantes de la maladie, bien que les taux soient demeurés plus élevés que les valeurs souhaitées. La faible absorption d'acide phytanique fut obtenue par réduction alimentaire des graisses totales à 10 à 12g/jour, liberté d'absorption pour les fruits et légumes verts. ZUSAMMENFASSUNG Ein Kind mit Refsum Krankheit: erfolgreiche Therapie mit Diät und Plasmaaustausch Ein Kind mit Refsum Krankheit kam mit kardialer Dekompensation, ausgeprägtem Muskelschwund, Schwäche und Koordinationsstörungen. Durch eine Behandlung mit mehrfachem Plasmaaustausch und Phytansäure armer Diät konnten die Symptome der Erkrankung deutlich gebessert werden, obwohl die Phytansäurespiegel höher als die Zielwerte blieben. Eine niedrige Aufnahme von Phytansäure wird durch eine Einschränkung des Gesamtfettes auf 10 bis 20g/Tag erreicht, während Früchte und grünes Gemüse ad libitum erlaubt sind. RESUMEN Niño con enfermedad de Refsum: éxito del tratamiento con dieta y cambio de plasma Un niño con enfermedad de Refsum presentaba fallo cardíaco, atrofia muscular marcada, debilidad e incoordinación. El tratamiento con múltiples cambios de plasma y restricción dietética de áido fitánico ha hecho retroceder las caracteristicas minusvalentes de la enfermedad, si bien los niveles todavia son más altos que los de referencia. Un ingreso bajo de acido fitánico se consigue con la restricción de la grasa total a 10 a 12 g por dia, al mismo tiempo que se permiten cantidades libres de frutos y vegetales verdes.

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“…Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid that originates from phytol, a breakdown product of the chlorophyll molecule. Mammals are able to take up free phytol from the diet and convert it into phytanic acid or directly take up phytanic acid.…”

Section: Supplementary Abstract Fatty Acids • Cytochrome P450 • -Oximentioning

confidence: 99%

“…In previous studies, presumed metabolites of phytanic acid -oxidation have been identified in urine of patients suffering from ARD, including 3-methylhexanedioic acid (3-methyladipic acid) and 2,6-dimethyloctanedioic acid (2,6-dimethylsuberic acid) (11)(12)(13)(14). These metabolites are virtually undetectable in urine from normal individuals.…”

Section: Supplementary Abstract Fatty Acids • Cytochrome P450 • -Oximentioning

confidence: 99%

ω-Hydroxylation of phytanic acid in rat liver microsomes

Komen

Durán

Wanders

2004

Journal of Lipid Research

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The 3-methyl-branched fatty acid phytanic acid is degraded by the peroxisomal ␣ -oxidation route because the 3-methyl group blocks ␤ -oxidation. In adult Refsum disease (ARD), peroxisomal ␣ -oxidation is defective, which is caused by mutations in the gene coding for phytanoyl-CoA hydroxylase in the majority of ARD patients. As a consequence, phytanic acid accumulates in tissues and body fluids. This study focuses on an alternative route of phytanic acid degradation, -oxidation. The first step in -oxidation is hydroxylation at the -end of the fatty acid, catalyzed by a member of the cytochrome P450 multienzyme family. To study this first step, the formation of hydroxylated intermediates was studied in rat liver microsomes incubated with phytanic acid and NADPH. Two hydroxylated metabolites of phytanic acid were formed, -and ( -1)-hydroxyphytanic acid (ratio of formation, 5:1). The formation of -hydroxyphytanic acid was NADPH dependent and inhibited by imidazole derivatives. These results indicate that phytanic acid undergoes -hydroxylation in rat liver microsomes and that an isoform of cytochrome P450 catalyzes the first step of phytanic acid -oxidation.

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Metabolism of Phytanic Acid in Refsum's Disease

Cited by 23 publications

References 9 publications

Identification of the cytochrome P450 enzymes responsible for the ω‐hydroxylation of phytanic acid

Identification of the cytochrome P450 enzymes responsible for the ω‐hydroxylation of phytanic acid

A Child with Refsum's Disease: Successful Treatment with Diet and Plasma Exchange

ω-Hydroxylation of phytanic acid in rat liver microsomes

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