Advertisement
J. Lipid Res.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1194/jlr.M400064-JLR200 on April 21, 2004

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
M400064-JLR200v1
45/7/1341    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Komen, J. C.
Right arrow Articles by Wanders, R. J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Komen, J. C.
Right arrow Articles by Wanders, R. J. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Journal of Lipid Research, Vol. 45, 1341-1346, July 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

{omega}-Hydroxylation of phytanic acid in rat liver microsomes

: implications for Refsum disease

J. C. Komen, M. Duran and R. J. A. Wanders1

University of Amsterdam, Academic Medical Center, Departments of Clinical Chemistry and Pediatrics, Emma Children's Hospital, Laboratory for Genetic Metabolic Diseases, Amsterdam, the Netherlands

Published, JLR Papers in Press, May 1, 2004. DOI 10.1194/jlr.M400064-JLR200

1 To whom correspondence should be addressed. e-mail: r.j.wanders{at}amc.uva.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
The 3-methyl-branched fatty acid phytanic acid is degraded by the peroxisomal {alpha}-oxidation route because the 3-methyl group blocks ß-oxidation. In adult Refsum disease (ARD), peroxisomal {alpha}-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, {omega}-oxidation. The first step in {omega}-oxidation is hydroxylation at the {omega}-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, {omega}- and ({omega}-1)-hydroxyphytanic acid (ratio of formation, 5:1). The formation of {omega}-hydroxyphytanic acid was NADPH dependent and inhibited by imidazole derivatives.

These results indicate that phytanic acid undergoes {omega}-hydroxylation in rat liver microsomes and that an isoform of cytochrome P450 catalyzes the first step of phytanic acid {omega}-oxidation.

Abbreviations: ARD, adult Refsum disease; TMS, trimethylsilyl

Supplementary key words fatty acids • cytochrome P450 • {omega}-oxidation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
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. In general, branched-chain fatty acids are degraded by the ß-oxidation pathway in peroxisomes and mitochondria (1). However, this is only true for 2-methyl branched-chain fatty acids. Phytanic acid contains a methyl group at the third carbon atom that blocks ß-oxidation. As with other 3-methyl branched fatty acids, phytanic acid degradation proceeds primarily via {alpha}-oxidation. During {alpha}-oxidation, phytanic acid is shortened by one carbon atom (the {alpha}-carbon) at the carboxyl end to produce its n-1 analog pristanic acid (2,6,10,14-tetramethylpentadecanoic acid). This fatty acid has a 2-methyl group and can be further degraded by ß-oxidation (2–4).

In adult Refsum disease (ARD), the {alpha}-oxidation pathway is deficient. In the majority of ARD patients this is attributable to mutations in the gene coding for the first enzyme in this pathway, phytanoyl-CoA hydroxylase (5–7). As a consequence, phytanic acid accumulates in ARD patients. This accumulation of phytanic acid is generally used as the biochemical marker of ARD and is believed to be the major cause of the pathology. The symptoms include retinitis pigmentosa, peripheral neuropathy, and cerebellar ataxia (2). Treatment of ARD consists of a diet low in phytanic acid, which may be accompanied by plasmapheresis.

Fatty acids may not only undergo {alpha}- and/or ß-oxidation but also {omega}-oxidation. In this pathway, the carbon atom at the {omega}-end of the fatty acid is hydroxylated by a member of the cytochrome P450 enzyme family. This hydroxylated fatty acid is then converted into an aldehyde by an alcohol dehydrogenase, and subsequently this aldehyde is converted into a carboxyl group by an aldehyde dehydrogenase. As a consequence, the final product of the pathway is a dicarboxylic fatty acid, which can be degraded further by ß-oxidation from the {omega}-end.

{omega}-Oxidation of fatty acids, prostaglandins, and leukotrienes by members of the cytochrome P450 family has been extensively investigated (8, 9), but there is hardly any data on the {omega}-oxidation of phytanic acid except from a single report dating from 1968 (10). In previous studies, presumed metabolites of phytanic acid {omega}-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) (11–14). These metabolites are virtually undetectable in urine from normal individuals.

The fact that phytanic acid {omega}-oxidation may occur in ARD patients could be a starting point of an alternative treatment of the disease based on the induction of phytanic acid {omega}-oxidation. This hypothesis is all the more attractive because a general characteristic of the cytochrome P450 family is its inducibility by a wide variety of drugs. For this reason, we have studied phytanic acid {omega}-oxidation, paying particular attention to the first step: the hydroxylation of phytanic acid. The results are described below.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 REFERENCES
 
Materials
Phytanic acid and 3-hydroxyheptadecanoic acid were purchased from Larodan Fine Chemicals AB (Malmö, Sweden). NADPH and NAD+ were obtained from Roche (Mannheim, Germany). Clotrimazole, ketoconazole, bifonozole, and miconazole were purchased from Sigma (St. Louis, MO). Methyl-ß-cyclodextrin was from Fluka (Buchs, Switzerland).

Preparation of rat liver microsomes
Microsomes were isolated from rat livers by differential centrifugation essentially as described by Baudhuin et al. (15). To this end, male Wistar rats fed a standard laboratory diet were fasted overnight before killing and removal of the liver. The livers were rapidly chilled and washed several times in buffer containing 250 mM sucrose, 0.5 mM EDTA, and 2 mM MOPS/KOH (final pH 7.4). Subsequently, the livers were minced and homogenized with a Potter S homogenizer (B. Braun) with a Teflon pestle at 500 rpm (five strokes), followed by centrifugation of the homogenate for 10 min at 550 g. The obtained postnuclear supernatant was subjected to centrifugation at 22,500 g for 10 min to remove mitochondria and lysosomes. Finally, the microsomal fraction was obtained by centrifugation of the supernatant for 3 h at 32,000 g. The microsomal pellet fraction was taken up in PBS containing 5 mM DTT and divided into small aliquots, which were stored at –80°C. The microsomes were sonicated three times for 10 s at 8 W before each experiment. The protein concentration of the microsomal fraction was determined with the method described by Bradford (16).

Phytanic acid {omega}(-1)-hydroxylase assay
The standard reaction mixture consisted of 100 mM potassium phosphate buffer, pH 7.4, and rat liver microsomes (1 mg/ml end concentration) plus phytanic acid dissolved in DMSO (200 µM end concentration, unless indicated otherwise). Reactions were initiated by the addition of NADPH at a final concentration of 1 mM. The final reaction volume was 0.2 ml. Reactions were terminated by the addition of 0.2 ml of 1 M HCl. Subsequently, 1 ml of PBS was added followed by the addition of 0.1 ml of 12.1 M HCl. The internal standard (10 nmol of 3-hydroxyheptadecanoic acid in 20 µl of ethanol) was added to this aqueous mixture. The samples were extracted twice with 6 ml of ethylacetate-diethylether (1:1, v/v). The organic layer was collected, and the solvents were evaporated under vacuum using a rotary evaporator at room temperature. The residue was dissolved in 4 ml of ethylacetate and further dried with MgSO4. After spinning down the MgSO4, the solution was transferred to 4 ml reaction vials, and the solvent was evaporated under nitrogen. To enable GS-MS analysis, the extracted fatty acids were derivatized to their corresponding trimethylsilyl (TMS) compounds essentially using the procedure described by Chalmers and Lawson (17). TMS ester/ether formation was performed with 40 µl of N,O-bis-(trimethylsilyl)trifluoroacetamide containing 1% trimethylchlorosilane and 10 µl of pyridine. The vials were sealed with a Teflon-lined screw cap and incubated at 80°C for 1 h. After the incubation, the solution could be directly used for GC-MS analysis.

GC-MS
GC-MS was performed on a Hewlett-Packard 6890 gas chromatograph coupled to a Hewlett-Packard 5973 mass-selective detector (Palo Alto, CA). Samples (1 µl) were injected in the splitless mode (Hewlett Packard 7683 injector) and analyzed on a CP-Sil 5 CB low-bleed mass spectrometer column (25 m x 0.30 µm) (Chrompack, Middelburg, The Netherlands). The oven temperature was programmed as follows: 70°C for 2 min, 5°C/min to 120°C, 7°C/min to 260°C, 3.5 min hold at 260°C, 15°C/min to 275°C, and hold for 10 min. The identities of the substrate, the internal standard, and the reaction product(s) were verified by taking mass spectra of the pertrimethylsilylated derivatives in the scanning electron impact mode. The single ion monitoring mode was applied for the detection of the respective (M-15)+ ions [m/z 369 and 457; masses of the molecular ions minus one methyl group of the TMS derivatives of phytanic acid and {omega}(-1)-hydroxyphytanic acid, respectively]. Analyte quantification was done by integration of the peaks followed by dividing the analyte peak areas with the area of the internal standard (TMS derivative of 3-hydroxyheptadecanoic acid, monitored ion m/z 233).


   RESULTS AND DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
REFERENCES
 
Hydroxylation of phytanic acid by rat liver microsomes
To study the {omega}-oxidation of phytanic acid, rat liver microsomes were incubated in a phosphate-buffered medium containing phytanic acid. When NADPH was added, two products appeared in the chromatogram, one with a retention time of 29.1 min and the other with a retention time of 29.7 min (Fig. 1) . The major peak was identified as {omega}-hydroxyphytanic acid (16-hydroxyphytanic acid) according to its mass spectrum (Fig. 2A) . Mass spectral analysis of this peak revealed the presence of a fragment (m/z 103) characteristic for {omega}-hydroxy acids, representing the terminal CH2OSi(CH3)3 moiety (18). The minor peak corresponds to ({omega}-1)-hydroxyphytanic acid (15-hydroxyphytanic acid) (Fig. 2B), the product of ({omega}-1)-hydroxylation. A general characteristic of the TMS derivatives of the hydroxy fatty acids is cleavage of the molecule adjacent to the hydroxyl group (19). It was deduced from the mass spectrum in Fig. 2B that the base peak at m/z 131 represents the (CH3)2COSi(CH3)3 moiety, in analogy with the mass spectrum of 3-hydroxyisovaleric acid.



View larger version (11K):
[in this window]
[in a new window]
  		Fig. 1. GC-MS (single-ion monitoring mode) chromatograms of extracts from rat liver microsomes incubated with phytanic acid in the absence (A) or presence (B) of NADPH. Spectrum analysis was done as described in Materials and Methods. Peaks corresponding to the (M-15)+ (m/z 457) of hydroxylated phytanic acid metabolites are labeled I and II. 3-Hydroxyheptadecanoic acid (ion m/z 233) was used as the internal standard (IS).

 


View larger version (20K):
[in this window]
[in a new window]
  		Fig. 2. Mass spectra of peaks labeled I and II in Fig. 1B. Based on the fragmentation patterns shown in A and B, peak I was identified as the trimethylsilyl (TMS) derivative of ({omega}-1)-hydroxyphytanic acid, whereas peak II was identified as the TMS-derivative of {omega}-hydroxyphytanic acid.

 
Optimization of the hydroxylase assay
The hydroxylation assay was further optimized for the formation of {omega}-hydroxyphytanic acid. First, the influence of methyl-ß-cyclodextrin, added to increase solubilization of the substrate, on the formation of {omega}-hydroxyphytanic acid was tested (20, 21). Figure 3A shows that methyl-ß-cyclodextrin has a positive effect on the assay, with an optimum concentration of 0.75 mg/ml. Higher methyl-ß-cyclodextrin concentrations had a negative effect on the assay, presumably because of decreased substrate availability.



View larger version (23K):
[in this window]
[in a new window]
  		Fig. 3. Optimization of the phytanic acid hydroxylase activity in rat liver microsomes. A: The effect of different concentrations of methyl-ß-cyclodextrin on the formation of {omega}-hydroxyphytanic acid ({omega}-HPA) in rat liver microsomes was determined under the conditions described in Materials and Methods. B: The pH dependency of phytanic acid {omega}-hydroxylation. The hydroxylase assay was performed as in A, with the exception of the use of a combined buffer containing 50 mM potassium phosphate, 50 mM pyrophosphate, and 0.75 mg/ml methyl-ß-cyclodextrin. C: The effect of the NADPH concentration on phytanic acid {omega}-hydroxylation in the presence of a NADPH-regenerating system (10 mM isocitrate, 10 mM MgCl2, and 0.08 unit of isocitrate dehydrogenase). The experimental setup was as described in Materials and Methods, with the exception of using a 100 mM potassium phosphate buffer (pH 7.6) and 0.75 mg/ml methyl-ß-cyclodextrin. The Km for NADPH was determined to be 35 µM, as derived from the Lineweaver-Burk plot (inset). D: The effect of the phytanic acid concentration on the formation of {omega}-hydroxyphytanic acid was determined using the optimum experimental conditions derived from the previous experiments [100 mM potassium phosphate buffer (pH 7.6) and 1 mM NADPH]. The ratio of methyl-ß-cyclodextrin to phytanic acid was kept constant. All data shown represent means of duplicate experiments with the exception of Fig. 3C, in which 3–4 separate experiments were done with the SD values shown as error bars.

 
To determine the optimal pH value for our assay, a combined buffer system with 50 mM potassium phosphate and 50 mM pyrophosphate was used to cover the pH range 6.6–9.1. The result depicted in Fig. 3B shows an optimum pH of 7.6. Accordingly, all subsequent experiments were performed in 0.1 M potassium phosphate at pH 7.6.

Our next aim was to analyze the kinetics of the hydroxylation of phytanic acid under the conditions determined in the previous experiments. We already established that NADPH was an essential component of the reaction mixture (Fig. 1). The NADPH dependency of the reaction was studied in more detail by performing the assay at different NADPH concentrations. For this purpose, we included a NADPH-regenerating system (10 mM isocitrate, 10 mM MgCl2, and 0.08 unit of isocitrate dehydrogenase) in the assay mixture, because large amounts NADPH were consumed during the assay (data not shown). The formation of {omega}-hydroxyphytanic acid followed simple Michaelis-Menten kinetics (Fig. 3C). The apparent Km for NADPH derived from the Lineweaver-Burk plot (inset in Fig. 3C) was 35 µM.

Subsequently, we determined the effect of increasing phytanic acid concentrations on the formation of {omega}-hydroxyphytanic acid. To this end, different concentrations of phytanic acid were added in a fixed molar ratio between phytanic acid and methyl-ß-cyclodextrin (Fig. 3D). An apparent Km of 114 ± 9 µM was found.

Based on the experiments described above, we selected the following assay conditions: 0.75 mg/ml methyl-ß-cyclodextrin,100 mM potassium phosphate (pH 7.6), 1 mM NADPH, and 200 µM phytanic acid. Under these conditions, the formation of {omega}-hydroxyphytanic acid was linear with time up to 60 min and with protein up to 1 mg/ml (data not shown).

Effect of imidazole derivatives on the formation of {omega}-hydroxyphytanic acid
Imidazole antimycotics are known inhibitors of cytochrome P450 enzymes (22–24). To measure the influence of four different imidazole derivatives on the formation of {omega}-hydroxyphytanic acid, we studied the effects of different concentrations of these compounds on the formation of {omega}-hydroxyphytanic acid (Fig. 4A) and ({omega}-1)-hydroxyphytanic acid (Fig. 4B). Figure 4A shows that {omega}-hydroxyphytanic acid formation was inhibited by all four compounds, with bifonazole as the most potent inhibitor, followed by ketoconazole, miconazole, and clotrimazole. Interestingly, a different picture was observed if the effect of the four imidazole derivatives was studied on the formation of the ({omega}-1) compound, with miconazole as most potent inhibitor, followed by ketoconazole and bifonazole. Remarkably, clotrimazole showed a stimulatory effect at low concentrations, with little inhibition at the highest concentrations used (100 µM).



View larger version (19K):
[in this window]
[in a new window]
  		Fig. 4. Effect of different imidazole antimycotics on the {omega}- and ({omega}-1)-hydroxylation of phytanic acid. Rat liver microsomes were incubated with phytanic acid in the presence of different concentrations of imidazole derivatives. The inhibitory effect of the imidazole derivatives on the formation of {omega}-hydroxyphytanic acid ({omega}-HPA; A) and ({omega}-1)-hydroxyphytanic acid (B) is shown. The data shown represent means of duplicate experiments.

 
To summarize, phytanic acid is hydroxylated to its {omega}- and ({omega}-1)-hydroxy analogs in rat liver microsomes. The enzyme(s) responsible for phytanic acid {omega}- and ({omega}-1)-hydroxylation were shown to be NADPH dependent. Moreover, the formation of the {omega}- and ({omega}-1)-hydroxy analogs of phytanic acid was inhibited by imidazole antimycotics. The inhibition by the imidazole derivatives showed a different pattern for the two products. This strongly suggests that different members of the cytochrome P450 multienzyme family are responsible for the formation of {omega}- and ({omega}-1)-phytanic acid. Future work is aimed at the identification of the specific cytochrome P450s involved and the resolution of the subsequent metabolism of {omega}-hydroxyphytanic acid. Preliminary results have already shown the formation of the dicarboxylic acid of phytanic acid. Furthermore, we will study whether phytanic acid {omega}-oxidation can be induced to generate a new therapeutic option for Refsum disease patients by induction of the capacity to {omega}-oxidize phytanic acid.


   ACKNOWLEDGMENTS
 
The authors gratefully thank Daan van den Brink, Sacha Ferdinandusse, Rob Ofman, Joram van Miert, and Gerbert Jansen for helpful discussions and help at various stages of these studies. This work was financially supported by the European Union (Project QLG3-2002-00696).

Submitted on February 17, 2004
Revised on April 13, 2004


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
  1. Wanders, R. J., P. Vreken, S. Ferdinandusse, G. A. Jansen, H. R. Waterham, C. W. van Roermund, and E. G. Van Grunsven. 2001. Peroxisomal fatty acid alpha- and beta-oxidation in humans: enzymology, peroxisomal metabolite transporters and peroxisomal diseases. Biochem. Soc. Trans. 29: 250–267.[CrossRef][Medline]

  2. Wanders, R. J., C. Jakobs, and O. H. Skjeldal. 2001. Refsum disease. In The Metabolic and Molecular Bases of Inherited Disease. C. R. Scriver, A. L. Beaudet, D. Valle, and W. S. Sly, editors. McGraw-Hill, New York. 3303–3322.

  3. Mukherji, M., C. J. Schofield, A. S. Wierzbicki, G. A. Jansen, R. J. Wanders, and M. D. Lloyd. 2003. The chemical biology of branched-chain lipid metabolism. Prog. Lipid Res. 42: 359–376.[CrossRef][Medline]

  4. Wierzbicki, A. S., M. D. Lloyd, C. J. Schofield, M. D. Feher, and F. B. Gibberd. 2002. Refsum's disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation. J. Neurochem. 80: 727–735.[CrossRef][Medline]

  5. Jansen, G. A., R. Ofman, S. Ferdinandusse, L. Ijlst, A. O. Muijsers, O. H. Skjeldal, O. Stokke, C. Jakobs, G. T. Besley, J. E. Wraith, and R. J. Wanders. 1997. Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nat. Genet. 17: 190–193.[CrossRef][Medline]

  6. Jansen, G. A., R. J. Wanders, P. A. Watkins, and S. J. Mihalik. 1997. Phytanoyl-coenzyme A hydroxylase deficiency—the enzyme defect in Refsum's disease. N. Engl. J. Med. 337: 133–134.[Free Full Text]

  7. Mihalik, S. J., J. C. Morrell, D. Kim, K. A. Sacksteder, P. A. Watkins, and S. J. Gould. 1997. Identification of PAHX, a Refsum disease gene. Nat. Genet. 17: 185–189.[CrossRef][Medline]

  8. Okita, R. T., and J. R. Okita. 2001. Cytochrome P450 4A fatty acid omega hydroxylases. Curr. Drug Metab. 2: 265–281.[CrossRef][Medline]

  9. Simpson, A. E. 1997. The cytochrome P450 4 (CYP4) family. Gen. Pharmacol. 28: 351–359.[Medline]

  10. Try, K. 1968. The in vitro omega-oxidation of phytanic acid and other branched chain fatty acids by mammalian liver. Scand. J. Clin. Lab. Invest. 22: 224–230.[Medline]

  11. Billimoria, J. D., M. E. Clemens, F. B. Gibberd, and M. N. Whitelaw. 1982. Metabolism of phytanic acid in Refsum's disease. Lancet. 1: 194–196.[CrossRef][Medline]

  12. Brenton, D. P., and S. Krywawych. 1982. 3-Methyladipate excretion in Refsum's disease. Lancet. 319: 624.

  13. Greter, J., S. Lindstedt, and G. Steen. 1983. 2,6-Dimethyloctanedioic acid—a metabolite of phytanic acid in Refsum's disease. Clin. Chem. 29: 434–437.[Abstract/Free Full Text]

  14. Wierzbicki, A. S., P. D. Mayne, M. D. Lloyd, D. Burston, G. Mei, M. C. Sidey, M. D. Feher, and F. B. Gibberd. 2003. Metabolism of phytanic acid and 3-methyl-adipic acid excretion in patients with adult Refsum disease. J. Lipid Res. 44: 1481–1488.[Abstract/Free Full Text]

  15. Baudhuin, P., H. Beaufay, Y. Rahman-Li, O. Z. Sellinger, R. Wattiaux, P. Jacques, and C. De Duve. 1964. Tissue fractionation studies. 17. Intracellular distribution of monoamine oxidase, aspartate aminotransferase, alanine aminotransferase, D-amino acid oxidase and catalase in rat-liver tissue. Biochem. J. 92: 179–184.[Medline]

  16. Bradford, M. M. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248–254.[CrossRef][Medline]

  17. Chalmers, R. A., and A. M. Lawson. 1982. Organic Acids in Man: The Analytical Chemistry, Biochemistry and Diagnosis of the Organic Acidurias. Chapman and Hall, London.

  18. Jakobs, C., M. Bojasch, E. Monch, D. Rating, H. Siemes, and F. Hanefeld. 1981. Urinary excretion of gamma-hydroxybutyric acid in a patient with neurological abnormalities. The probability of a new inborn error of metabolism. Clin. Chim. Acta. 111: 169–178.[CrossRef][Medline]

  19. Mamer, O. A., J. A. Montgomery, and E. Colle. 1980. Profiles in altered metabolism. II. (Omega-1)-hydroxyacid excretion in a case of episodic hypoglycemia. Biomed. Mass Spectrom. 7: 53–57.[CrossRef][Medline]

  20. Muralidharan, V. B., and Y. Kishimoto. 1984. Phytanic acid alpha-oxidation in rat liver. Requirement of cytosolic factor. J. Biol. Chem. 259: 13021–13026.[Abstract/Free Full Text]

  21. Singh, I., and Y. Kishimoto. 1983. Effect of cyclodextrins on the solubilization of lignoceric acid, ceramide, and cerebroside, and on the enzymatic reactions involving these compounds. J. Lipid Res. 24: 662–665.[Abstract]

  22. Halpert, J. R. 1995. Structural basis of selective cytochrome P450 inhibition. Annu. Rev. Pharmacol. Toxicol. 35: 29–53.[CrossRef][Medline]

  23. Zhang, W., Y. Ramamoorthy, T. Kilicarslan, H. Nolte, R. F. Tyndale, and E. M. Sellers. 2002. Inhibition of cytochromes P450 by antifungal imidazole derivatives. Drug Metab. Dispos. 30: 314–318.[Abstract/Free Full Text]

  24. Maurice, M., L. Pichard, M. Daujat, I. Fabre, H. Joyeux, J. Domergue, and P. Maurel. 1992. Effects of imidazole derivatives on cytochromes P450 from human hepatocytes in primary culture. FASEB J. 6: 752–758.[Abstract]


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
B. Ashibe, T. Hirai, K. Higashi, K. Sekimizu, and K. Motojima
Dual Subcellular Localization in the Endoplasmic Reticulum and Peroxisomes and a Vital Role in Protecting against Oxidative Stress of Fatty Aldehyde Dehydrogenase Are Achieved by Alternative Splicing
J. Biol. Chem., July 13, 2007; 282(28): 20763 - 20773.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
F. Xu, V. Y. Ng, D. L. Kroetz, and P. R. O. de Montellano
CYP4 Isoform Specificity in the {omega}-Hydroxylation of Phytanic Acid, a Potential Route to Elimination of the Causative Agent of Refsum's Disease
J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 835 - 839.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
M400064-JLR200v1
45/7/1341    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Komen, J. C.
Right arrow Articles by Wanders, R. J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Komen, J. C.
Right arrow Articles by Wanders, R. J. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Journal of Biological Chemistry 
 Molecular and Cellular Proteomics   ASBMB Today 
Advertisement
spacer
Advertisement
Advertisement