ω-Hydroxylation of phytanic acid in rat liver microsomes

Komen, J.C.; Durán, Marinus; Wanders, Ronald J. A.

doi:10.1194/jlr.m400064-jlr200

Cited by 24 publications

(25 citation statements)

References 23 publications

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“…1A. The spectrum depicts a prominent loss of H 35 Cl from the [M Ϫ H] Ϫ ion. A similar facile loss of HCl has been described previously for 2-ClHA (23).…”

Section: Resultsmentioning

confidence: 99%

“…2-ClAdA gradient 2 was performed at 300 l/min as follows: 0 -4 min 100% A to 90% A, 4 -12 min 90% A to 20% A, 12-18 min 20% A to 0% A, 18 -23 min 0% A, 23-24 min 0% A to 100% A, and 24 -35 min 100% A for re-equilibration. For both elution gradients, the transitions from m/z 179 3 143 for 2- 35 ClAdA and m/z 181 3 143 for 2- 37 ClAdA were monitored in the negative ion mode. For stable isotope-labeled 2-ClAdA, the following SRMs were used: m/z 181 3 145 for 2- For some analyses, as indicated, ESI-MS/MS was also performed on analytes in methanol.…”

Section: Esi-ms/ms and Lc-ms/ms-formentioning

confidence: 99%

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ω-Oxidation of α-Chlorinated Fatty Acids

Brahmbhatt

Albert

Anbukumar

et al. 2010

Journal of Biological Chemistry

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Myeloperoxidase-derived HOCl targets tissue-and lipoprotein-associated plasmalogens to generate ␣-chlorinated fatty aldehydes, including 2-chlorohexadecanal. Under physiological conditions, 2-chlorohexadecanal is oxidized to 2-chlorohexadecanoic acid (2-ClHA). This study demonstrates the catabolism of 2-ClHA by -oxidation and subsequent ␤-oxidation from the -end. Mass spectrometric analyses revealed that 2-ClHA is -oxidized in the presence of liver microsomes with initial -hydroxylation of 2-ClHA. Subsequent oxidation steps were examined in a human hepatocellular cell line (HepG2). Three different ␣-chlorinated dicarboxylic acids, 2-chlorohexadecane-(1,16)-dioic acid, 2-chlorotetradecane-(1,14)-dioic acid, and 2-chloroadipic acid (2-ClAdA), were identified. Levels of 2-chlorohexadecane-(1,16)-dioic acid, 2-chlorotetradecane-(1,14)-dioic acid, and 2-ClAdA produced by HepG2 cells were dependent on the concentration of 2-ClHA and the incubation time. Synthetic stable isotope-labeled 2-ClHA was used to demonstrate a precursorproduct relationship between 2-ClHA and the ␣-chlorinated dicarboxylic acids. We also report the identification of endogenous 2-ClAdA in human and rat urine and elevations in stable isotopelabeled urinary 2-ClAdA in rats subjected to intraperitoneal administration of stable isotope-labeled 2-ClHA. Furthermore, urinary 2-ClAdA and plasma 2-ClHA levels are increased in LPStreated rats. Taken together, these data show that 2-ClHA is -oxidized to generate ␣-chlorinated dicarboxylic acids, which include ␣-chloroadipic acid that is excreted in the urine.

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“…1A. The spectrum depicts a prominent loss of H 35 Cl from the [M Ϫ H] Ϫ ion. A similar facile loss of HCl has been described previously for 2-ClHA (23).…”

Section: Resultsmentioning

confidence: 99%

Section: Esi-ms/ms and Lc-ms/ms-formentioning

confidence: 99%

ω-Oxidation of α-Chlorinated Fatty Acids

Brahmbhatt

Albert

Anbukumar

et al. 2010

Journal of Biological Chemistry

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“…GC-MS Analysis-GC-MS was performed according to a published method (30) with modifications on an Agilent GC6890 gas chromatographer coupled to a JMS-AM150 mass spectrometer (Jeol, Tokyo, Japan). A 30-m HP-5 column (0.32-mm inner diameter with 0.25-m filter, Agilent) was used with helium as the carrier gas.…”

Section: Methodsmentioning

confidence: 99%

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

Ashibe

Hirai

Higashi

et al. 2007

Journal of Biological Chemistry

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Fatty aldehyde dehydrogenase (FALDH, ALDH3A2) is thought to be involved in the degradation of phytanic acid, a saturated branched chain fatty acid derived from chlorophyll. However, the identity, subcellular distribution, and physiological roles of FALDH are unclear because several variants produced by alternative splicing are present in varying amounts at different subcellular locations. Subcellular fractionation experiments do not provide a clear-cut conclusion because of the incomplete separation of organelles. We established human cell lines heterologously expressing mouse FALDH from each cDNA without tagging under the control of an inducible promoter and detected the variant FALDH proteins using a mouse FALDHspecific antibody. One variant, FALDH-V, was exclusively detected in peroxisomal membranes. Human FALDH-V with an amino-terminal Myc sequence also localized to peroxisomes. The most dominant form, FALDH-N, and other variants examined, however, were distributed in the endoplasmic reticulum. A gas chromatography-mass spectrometry-based analysis of metabolites in FALDH-expressing cells incubated with phytol or phytanic acid showed that FALDH-V, not FALDH-N, is the key aldehyde dehydrogenase in the degradation pathway and that it protects peroxisomes from oxidative stress. In contrast, both FALDHs had a protective effect against oxidative stress induced by a model aldehyde for lipid peroxidation, dodecanal. These results suggest that FALDH variants are produced by alternative splicing and share an important role in protecting against oxidative stress in an organelle-specific manner.Plants produce a variety of secondary metabolites, and some of these are potentially toxic to animals (1). Herbivora have developed behavioral and physiological strategies to avoid specific plants and to detoxify any toxins ingested. Detoxification can occur in the mouth and the gut rumen with or without the help of microbes (2). The absorbed toxins must be detoxified in the intestine and liver, but studies on these mechanisms are limited because to date most animal experiments have been carried out using laboratory diets. Recently we found that a nuclear receptor, peroxisome proliferator-activated receptor ␣ (PPAR␣), 2 is involved in the detoxification by using plant seeds as a diet for mice (3).PPAR␣ is activated by fatty acid ligands and is an important regulator of lipid metabolism in animals (4). Despite the claimed essential role of this receptor in the liver, the PPAR␣-null mouse shows little phenotypic change when fed a normal laboratory diet (5, 6). We have examined its extrahepatic roles and found that PPAR␣ induces the expression of 17␤-hydroxysteroid dehydrogenase type 11 in the intestine (7). Recent studies on the substrates of 17␤-hydroxysteroid dehydrogenase type 11 showed that they include not only glucocorticoids and sex steroids but also bile acids, fatty acids, and branched amino acids (8, 9). So we examined the possibility that PPAR␣ plays a vital role in inducing enzymes for metabolizing secondary metabolites...

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“…2C), although the peak is small in comparison with that of the -OH-PA (retention time ϭ 22.4 min, m/z ϭ 457, with a characteristic fragment of m/z ϭ 103, Fig. 2D) (Komen et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

“…Further oxidation of the terminal hydroxyl group to the acid, a reaction catalyzed by both the CYP4 enzymes and alcohol/aldehyde dehydrogenases (Sanders et al, 2005), produces dicarboxylic acids that can undergo ␤-oxidation from either end. It has been reported that phytanic acid can also be -hydroxylated, giving rise to an -hydroxy alcohol that, after oxidation to the acid, can be degraded normally by ␤-oxidation (Komen et al, 2004(Komen et al, , 2005. Studies of phytanic acid -hydroxylation have so far only been carried out with microsomal systems that do not allow identification of the actual enzymes involved in the reaction (Komen et al, 2004(Komen et al, , 2005.…”

mentioning

confidence: 99%

CYP4 Isoform Specificity in the ω-Hydroxylation of Phytanic Acid, a Potential Route to Elimination of the Causative Agent of Refsum's Disease

Ng²,

Kroetz³

et al. 2006

J Pharmacol Exp Ther

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The saturated C20 isoprenoid phytanic acid is physiologically derived from phytol released in the degradation of chlorophyll. The presence of a C-3 methyl group in this substrate blocks normal ␤-oxidation, so phytanic acid degradation primarily occurs by initial peroxisomal ␣-oxidation to shift the register of the methyl group. However, individuals with Refsum's disease are genetically deficient in the required phytanoyl-CoA ␣-hydroxylase and suffer from neurological pathologies caused by the accumulation of phytanic acid. Recent work has shown that phytanic acid can also be catabolized by a pathway initiated by -hydroxylation of the hydrocarbon chain, followed by oxidation of the alcohol to the acid and conventional ␤-oxidation. However, the enzymes responsible for the -hydroxylation of phytanic acid have not been identified. In this study, we have determined the activities of all of the rat and human CYP4A enzymes and two of the rat CYP4F enzymes, with respect to the -hydroxylation of phytanic acid. Furthermore, we have shown that the ability to -hydroxylate phytanic acid is elevated in microsomes from rats pretreated with clofibrate. The results support a possible role for CYP4 enzyme elevation in the elimination of phytanic acid in Refsum's disease patients.

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ω-Hydroxylation of phytanic acid in rat liver microsomes

Cited by 24 publications

References 23 publications

ω-Oxidation of α-Chlorinated Fatty Acids

ω-Oxidation of α-Chlorinated Fatty Acids

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

CYP4 Isoform Specificity in the ω-Hydroxylation of Phytanic Acid, a Potential Route to Elimination of the Causative Agent of Refsum's Disease

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