* Zentrumsabteilung für Lebensmitteltoxikologie, Zentrum für Lebensmittelwissenschaften, Tierärztliche Hochschule Hannover, Bischofsholer Damm 15, D-30173 Hannover, Germany; and
College of Pharmacy, Mansoura University, Mansoura, Egypt
Received August 16, 2001; accepted November 15, 2001
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: vitamin A; retinol; retinoic acid; phytol; phytanic acid; teratogenicity prevention; metabolism; retinoid receptors.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Besides 9-cis-retinoic acid, phytanic acid (Fig. 1) was identified as another natural ligand and transactivator of RXRs (LeMotte et al., 1996
). This compound is a branched chain fatty acid and an oxidation product of phytol (Fig. 1
), which is part of the chlorophyll molecule in fruits and vegetables (Steinberg, 1995
). It was demonstrated that the precursor phytol is bioactivated to phytanic acid in several species (Hansen et al., 1966
; Klenk and Kremer, 1965
; Mize et al., 1966
; Steinberg et al., 1966
; Stoffel and Kahlke, 1965
). In particular, phytanic acid itself occurs in substantial amounts in adipose tissues of ruminants because chlorophyll is efficiently degraded by ruminal bacteria, and the released phytol is absorbed and subsequently oxidized to phytanic acid (Avigan, 1966
). Therefore, high amounts of phytanic acid can be found in dairy products such as milk and butter. Phytanic acid is also present in human blood in µM concentrations (Steinberg, 1995
; Verhoeven et al., 1998
). Extremely high concentrations (mM levels) can be found in some disease states such as Refsum's disease or Zellweger syndrome, where dysfunction of phytanic acid
-oxidation leads to an accumulation of phytanic acid in human blood and tissues (Steinberg, 1995
; Verhoeven et al., 1998
). Interestingly, patients with these disorders displayed similar symptoms as described for vitamin A deficiency or hypervitaminosis A, such as retinitis pigmentosa and ichthyosis (Kaufman, 1998
; Stüttgen, 1982
; Van Soest et al., 1999
).
Simultaneous administration of phytanic acid and Am580 to pregnant mice led to a substantial potentiation of Am580-induced malformations, namely micrognathia (29 to 98%) and tail defects (7 to 98%). Although spina bifida did not occur when phytanic acid or Am580 were given alone, coadministration produced 51% of this type of malformation (Elmazar and Nau, 1998).
The present experiment, therefore, was designed to investigate whether the natural RXR ligand phytanic acid and its precursor, phytol, would interact with the natural RAR ligand all-trans-retinoic acid or its precursor retinol. To study metabolic interactions of these structurally similar lipophilic compounds, plasma pharmacokinetics in nonpregnant mice were additionally investigated. The bioactivation of retinol to all-trans-retinoic acid and its further metabolism to the phase I metabolites all-trans-4-oxo-retinoic acid and all-trans-4-hydroxy-retinoic acid as well as its phase II metabolite all-trans-RAG (all-trans-retinoyl-ß-glucuronide) was particularly analyzed.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals.
Female mice (NMRI: Harlan-Winkelmann, Borchen, Germany, 2935 g) were mated between 0600 and 0900 h. The animals with vaginal plugs were separated, and the first 24 h after conception were designated gestational day 0 (GD 0). The animals were allowed food (Altromin, 1324 diet, Lage, Germany) and water ad libitum and kept under controlled conditions of room temperature (21 ± 1°C), relative humidity (55 ± 5%), and a 12-h light/dark cycle, with light between 1000 and 2200 h.
Chemicals.
Phytol (3,7,11,15-tetramethyl-hexadec-2-ene-1-ol), phytanic acid (3,7,11,15-tetramethyl-hexadecanoic acid), all-trans-retinoic acid, retinol, and cremophor EL were purchased from Sigma (Deisenhofen, Germany). Unless otherwise indicated, retinoid standards for high performance liquid chromatography (HPLC) were purchased from Sigma. 14-Hydroxy-4,14-retro-retinol and anhydroretinol were generous gifts from Dr. F. Derguini (Memorial Sloan-Kettering Cancer Center, New York, NY). 4-Oxo- and 4-hydroxy-retinoic acid isomers were provided by Hoffmann-La Roche (Basel, Switzerland, and Nutley, NJ). Retinyl esters (except retinyl palmitate) and all-trans-retinoyl-ß-D-glucuronide (RAG) were synthesized in our laboratory while additional RAG was provided by Drs. A. B. Barua and J. A. Olson (Ames, IA). Methanol and isopropanol were of HPLC gradient-grade and obtained from Roth (Karlsruhe, Germany). Ethanol and ammonium acetate was purchased from Merck (Darmstadt, Germany). ß-Glucuronidase from E. coli (EC 3.2.1.31) was obtained from Boehringer Mannheim (Germany).
Drug administration.
Groups of mice were given a single po administration of either phytanic acid (100 mg/kg), phytol (500 mg/kg), all-trans-retinoic acid (20 mg/kg), or retinol (50 mg/kg) by gastric intubation on GD 8.25. For combination experiments, animals were given all-trans-retinoic acid or retinol simultaneously (in the same syringe) with either phytanic acid or phytol. Each agent was suspended in 25% cremophor EL in distilled water in concentrations so that each animal was administered 5 ml/kg. For pharmacokinetic investigations nonpregnant mice were treated as described for pregnant animals.
Fetal examination.
On GD 18, the pregnant animals were sacrificed by cervical dislocation. Implantation sites, resorptions, and live fetuses and resorptions were counted. Live fetuses were weighed individually and examined for external malformations. The results of the combination experiments were compared with the corresponding all-trans-retinoic acid or retinol group using two-tailed unpaired Student's t-test (fetal weight) or Fisher's exact test (malformations). All calculations were carried out using GraphPad InStat-2 Software (Jandel Co., San Raffael, CA).
Pharmacokinetic studies.
All-trans-retinoic acid or retinol was given alone or in combination with either phytanic acid or phytol to groups of nonpregnant mice (n = 3 per group and time point). Single blood samples of approximately 100150 µl were taken in heparinized capillary tubes from the retro-orbital sinus under brief ether anesthesia. Plasma was prepared by centrifugation of the blood for 10 min at 4°C and 1500 x g and stored at 80°C until analysis. Time intervals for blood collection were 0.5, 1, 2, and 4 h after administration of all-trans-retinoic acid alone or simultaneously with phytanic acid or phytol, and 2, 4, 8, and 12 h after administration of retinol alone or simultaneously with phytanic acid or phytol. Blood samples from untreated mice (n = 5) were also taken for determination of endogenous retinoid levels. Maximum concentrations (Cmax) were the observed values, and area under the concentration-time curve (AUC) values were calculated using the linear trapezoidal rule. Mean comparisons of concentration data were done using one-way ANOVA followed by Dunnett post hoc test; p values < 0.05 were considered significant.
HPLC analysis.
Plasma samples were extracted with a 3-fold volume of isopropanol and further submitted to solid-phase extraction according to a previously described method (Collins et al., 1992). A modification of the HPLC method described by Eckhoff and Nau (1990) was used for determination of plasma retinoids. This method used a linear gradient formed from 57.5% methanol and 42.5% aqueous 60 mM ammonium acetate (initial composition) to 95% methanol and 5 % ammonium acetate over 11 min. To also determine retinol and retinyl esters in a single chromatographic run, methanol percentage was increased to 100% at 11.2 min and further maintained at this level until 25 min (Tzimas et al., 1994
). The starting conditions of the gradient were reached again at 26 min. Detection was performed by simultaneous monitoring of the UV absorbance of the eluate at 340 and 356 nm using a Shimadzu SPD 10 AV detector (Kyoto, Japan). Due to the limited volume obtained from blood samples, the sample weight was 25 µl instead of 100 µl as described for the original method (Collins et al., 1992
). Therefore, the detection limit of retinoids was as follows: 9-cis-retinoic acid, all-trans-4-oxo-retinoic acid and 13-cis-4-oxo-retinoic acid, 2.8 ng/ml; 13-cis-retinoic acid and all-trans-retinoic acid, 2 ng/ml; RAG, 4 ng/ml; 14-HRR, 5 ng/ml; retinyl esters and anhydroretinol, 20 ng/ml. Peak eluates of putative retinoid glucuronides were collected, evaporated to dryness, redissolved in buffer, subjected to hydrolysis by ß-glucuronidase, after which the purified retinoids were rechromatographed. The procedure was described in detail by Sass et al. (1994).
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Coadministration of phytol decreased the number of resorptions (31%) significantly (p < 0.05). External abnormalities (4%) and exencephaly (14%) were slightly, but not significantly reduced. On the other hand, tail defects were not observed in this group. Spina bifida and micrognathia were found in 1 case each. Fetal weight (1.18 ± 0.12 g) was unaffected.
Teratogenic effects of retinol alone or coadministered with phytanic acid or phytol.
Administration of retinol (50 mg/kg orally on GD 8.25) resulted in a high number of resorptions (39%). Malformations seen in live fetuses included ear anotia (21%) and exencephaly (28%). Tail defects (1%) occurred in only 1 case, while spina bifida and micrognathia was not observed at all. Fetal weight was 1.23 ± 0.14 g (Fig. 3).
|
Coadministration of phytol with retinol led to a highly significant reduction of resorptions to 5% (p < 0.001). There were no external malformations. Fetal weight (1.29 ± 0.13 g) was significantly higher (p < 0.01) compared with the retinol group.
Endogenous retinoids in mouse plasma.
Retinol (180.1 ± 26.4 ng/ml), retinyl palmitate/oleate (116.4 ± 41.4 ng/ml), and retinyl stearate (52.1 ± 24.6 ng/ml) were detected in plasma of untreated, nonpregnant mice (n = 5). Additionally, retinyl linoleate (16.8 ± 4.1 ng/ml) was found in 2 plasma samples.
Plasma pharmacokinetics of all-trans-retinoic acid and its metabolites in nonpregnant mice.
Figure 4 displays a characteristic chromatogram of a plasma sample taken 1 h after dosing with all-trans-retinoic acid. All-trans-retinoic acid (7), 9-cis-retinoic acid (6), and 13-cis-retinoic acid (5) were identified by coelution with authentic retinoids. Additionally, the phase I metabolites all-trans-4-hydroxy-retinoic acid (2) and all-trans-4-oxo-retinoic acid (1) as well as the phase II metabolites 13-cis-RAG (3) and all-trans-RAG (4) were found (Table 2
). The identification of glucuronide metabolites was confirmed by treatment of peak eluates with ß-glucuronidase and subsequent detection of the retinoic acid isomers. The occurrence of all-trans-4-hydroxy-retinoic acid was further substantiated by LC-MS-MS (data not shown).
|
|
|
Plasma pharmacokinetics of retinol and its metabolites in nonpregnant mice.
After dosing with retinol, the dominant retinoid metabolites in plasma were retinol itself as well as the retinyl esters retinyl palmitate/oleate (not separable with our HPLC method), retinyl stearate, and retinyl linoleate (Fig. 6 and Table 3
). An oxidative metabolism of retinol was demonstrated by the occurrence of retinoic acid isomers (all-trans-, 13-cis-, and 9-cis-retinoic acid) and further metabolism led to the formation of all-trans-4-oxo-retinoic acid and all-trans-RAG. Additionally, the retro-retinoids anhydroretinol and 14-hydroxy-4,14-retro-retinol were detected (data not shown).
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Recent results show that all-trans-retinoic acid-induced as well as retinol-induced teratogenicity in mice is potentiated by coadministration of the synthetic RXR ligand LG1069 (Elmazar and Nau, 1998). In the same manner, embryotoxic effects of the synthetic RAR
ligand Am580 were potentiated by coadministration with phytanic acid and its precursor phytol (Elmazar and Nau, 1998
, unpublished observations). The results of the present study clearly demonstrate that embryotoxicity and teratogenicity of the natural RAR ligand all-trans-retinoic acid is not potentiated by the natural RXR ligand phytanic acid or by its precursor phytol. In contrast, coadministration of retinol, the precursor of all-trans-retinoic acid, with phytanic acid or phytol led to a pronounced reduction of retinol-induced teratogenic effects.
Investigations on metabolism and pharmacokinetics revealed that phytanic acid or phytol greatly decreases the formation of all-trans-retinoic acid from retinol. Furthermore, the oxidative metabolism of administered all-trans-retinoic acid to all-trans-4-oxo-retinoic acid was also decreased by phytanic acid and phytol coadministration.
On the other hand, phytanic acid has also been demonstrated to be a ligand of the peroxisome proliferator-activated receptor (PPAR
; Ellinghaus et al., 1999
; Wolfrum et al., 1999
). Therefore, it might be possible that phytanic acid acts as an RXR ligand in the presence of selective, synthetic RAR ligands, but as a PPAR
ligand in presence of the nonselective, natural RAR ligand all-trans-retinoic acid. Additionally, 9-cis-retinoic acid was detected as a metabolite of all-trans-retinoic acid in plasma of mice. This retinoid was reported to be 200-fold more potent than phytanic acid in mediating RXR-dependent transcriptional activity (Kitareewan et al., 1996
). Since it was shown that 9-cis-retinoic acid can induce RXR-homodimerization, the presence of the RXR ligand 9-cis-retinoic acid may have limited RXR availability for RAR-RXR heterodimerization.
The most surprising and important result of the present investigation was that phytanic acid, and in particular phytol, coadministration greatly reduced or completely abolished retinol-induced teratogenic effects. Pharmacokinetic studies clearly showed significantly reduced retinol Cmax and AUC values following coadministration of phytol (Fig. 6). Since it was shown in mice that phytol is absorbed via the lymphatic route (Baxter et al., 1967
), an interaction in absorption and further transport of retinoids in chylomicrons appears likely. Phytanic acid, and in particular phytol, coadministration additionally reduced the concentrations of the active ligand all-trans-retinoic acid (Fig. 6B
). Following coadministration of retinol and phytol, all-trans-retinoic acid formation was nearly undetectable and was reduced to half (p > 0.05) when phytanic acid was given with retinol (Table 3
). A steep dose-teratogenicity relationship for all-trans-retinoic acid is found in mice (Nau et al., 1994
); therefore, a slight reduction in all-trans-retinoic acid Cmax is expected to be accompanied by a higher reduction in teratogenicity. All-trans-retinoic acid (AUC) was also significantly reduced in the group given retinol and phytanic acid. Embryotoxicity of all-trans-retinoic acid is correlated to AUC rather than to Cmax (Tzimas et al., 1997
). Thus, metabolic interactions are mainly responsible for the reduction of retinol teratogenicity.
In vitro studies on metabolism of phytol showed that the bioconversion to phytanic acid via the intermediate phytenic acid occurred in mitochondrial and microsomal fractions of rat livers, respectively (Muralidharan and Muralidharan, 1985, 1986
). Cytosolic fractions had no activity. Furthermore, microsomal enzymes of the short chain alcohol dehydrogenase (SCAD) family were identified as retinol dehydrogenases in rat livers (Boerman and Napoli, 1995
; Chai et al., 1995
; Napoli, 1996
; Posch et al., 1991
). It remains to be investigated whether those enzymes that metabolize phytol or retinol might be identical. The oxidation of retinol to all-trans-retinoic acid via retinal as well as the 4-hydroxylation of all-trans-retinoic acid are known to be mediated by isoforms of P450 enzymes on endoplasmic reticulum (Roberts et al., 1979
, 1980
, 1992
). The main degradation of phytanic acid by
-oxidation seemed to be localized mainly in peroxisomes (Jansen et al., 1996
; Pahan and Singh, 1993
; Singh et al., 1993
; Wanders et al., 1994
), but activities were also found in microsomal fractions of human liver (Verhoeven et al., 1997
). The
-oxidation of phytanic acid, which is auto-inducible (Zomer et al., 2000
), was shown to be inhibited by ketoconazole (Pahan et al., 1994
) as well as by carbon monoxide (Muralidharan and Kishimoto, 1984
), both known to be strong inhibitors of cytochrome P450 mediated metabolism. It was furthermore demonstrated that the cytochrome P450BM-3, a prokaryotic P450 enzyme present in Bacillum megaterium ATCC14581 that resembles the isoforms of the P4504A family, was able to catalyze a phytanic acid
-hydroxylation and was itself inducible by phytanic acid (English et al., 1997
). The results point to interactions of the metabolic pathways of retinoid and phytanic acid/phytol metabolism.
Our results indicate a lack of synergism of the teratogenicity of retinol/retinoic acid, when coadministered with phytol/phytanic acid. Instead, phytol and phytanic acid effectively blocked the teratogenic activity induced by retinol via inhibition of the metabolism to all-trans-retinoic acid. Thus, phytol and phytanic acid may be useful for the prevention of vitamin A teratogenesis.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
NOTES |
---|
2 To whom correspondence should be addressed. Fax: +49-511-8567680. E-mail: heinz.nau{at}tiho-hannover.de.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Avigan, J. (1966). The presence of phytanic acid in normal human and animal plasma. Biochim. Biophys. Acta 116, 391394.[ISI][Medline]
Baxter, J. H., Steinberg, D., Mize, C. E., and Avigan, J. (1967). Absorption and metabolism of uniformly 14C-labeled phytol and phytanic acid by the intestine of the rat studied with thoracic duct cannulation. Biochim. Biophys. Acta. 137, 277290.[ISI][Medline]
Boerman, M. H., and Napoli, J. L. (1995). Characterization of a microsomal retinol dehydrogenase: A short-chain alcohol dehydrogenase with integral and peripheral membrane forms that interacts with holo-CRBP (type I). Biochemistry 34, 70277037.[ISI][Medline]
Chai, X., Zhai, Y., Popescu, G., and Napoli, J. L. (1995). Cloning of a cDNA for a second retinol dehydrogenase type II. Expression of its mRNA relative to type I. J. Biol. Chem. 270, 2840828412.
Chambon, P. (1993). The molecular and genetic dissection of the retinoid signalling pathway. Gene 135, 223228.[ISI][Medline]
Collins, M. D., Eckhoff, C., Chahoud, I., Bochert, G., and Nau, H. (1992). 4-Methylpyrazole partially ameliorated the teratogenicity of retinol and reduced the metabolic formation of all-trans-retinoic acid in the mouse. Arch. Toxicol. 66, 652659.[ISI][Medline]
Dolle, P., Ruberte, E., Leroy, P., Morriss-Kay, G., and Chambon, P. (1990). Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis. Development 110, 11331151.[Abstract]
Durand, B., Saunders, M., Leroy, P., Leid, M., and Chambon, P. (1992). All-trans and 9-cis retinoic acid induction of CRABPII transcription is mediated by RAR-RXR heterodimers bound to DR1 and DR2 repeated motifs. Cell 71, 7385.[ISI][Medline]
Durston, A. J., Timmermans, J. P., Hage, W. J., Hendriks, H. F., de Vries, N. J., Heideveld, M., and Nieuwkoop, P. D. (1989). Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature 340, 140144.[ISI][Medline]
Eckhoff, C., and Nau, H. (1990). Identification and quantitation of all-trans- and 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma. J. Lipid Res. 31, 14451454.[Abstract]
Ellinghaus, P., Wolfrum, C., Assmann, G., Spener, F., and Seedorf, U. (1999). Phytanic acid activates the peroxisome proliferator-activated receptor (PPAR
) in sterol carrier protein 2-/sterol carrier protein x-deficient mice. J. Biol. Chem. 274, 27662772.
Elmazar, M. M., and Nau, H. (1998). Synergistic teratogenic effects induced by combinations of synthetic and natural retinoids. Naunyn. Schmiedebergs Arch. Pharmacol. 358, R772 (Abstract).
Elmazar, M. M., Reichert, U., Shroot, B., and Nau, H. (1996). Pattern of retinoid-induced teratogenic effects: Possible relationship with relative selectivity for nuclear retinoid receptors RAR , RAR ß, and RAR
. Teratology 53, 158167.[ISI][Medline]
Elmazar, M. M. A., Rühl, R., and Nau, H. (2001). Synergistic teratogenic effect induced by retinoids in mice by coadministration of a RAR- or RAR
-selective agonist with a RXR-selective agonist. Toxicol. Appl. Pharmacol. 170, 29.[ISI][Medline]
Elmazar, M. M., Rühl, R., Reichert, U., Shroot, B., and Nau, H. (1997). RAR-mediated teratogenicity in mice is potentiated by an RXR agonist and reduced by an RAR antagonist: Dissection of retinoid receptor-induced pathways. Toxicol. Appl. Pharmacol. 146, 2128.[ISI][Medline]
English, N., Palmer, C. N., Alworth, W. L., Kang, L., Hughes, V., and Wolf, C. R. (1997). Fatty acid signals in Bacillus megaterium are attenuated by cytochrome P-450-mediated hydroxylation. Biochem. J. 327, 363368.[ISI][Medline]
Gudas, L. J. (1994). Retinoids and vertebrate development. J. Biol. Chem. 269, 1539915402.
Hansen, R. P., Shorland, F. B., and Prior, I. A. (1966). The fate of phytanic acid when administered to rats. Biochim. Biophys. Acta 116, 178180.[ISI][Medline]
Jansen, G. A., Mihalik, S. J., Watkins, P. A., Moser, H. W., Jakobs, C., Denis, S., and Wanders, R. J. (1996). Phytanoyl-CoA hydroxylase is present in human liver, located in peroxisomes, and deficient in Zellweger syndrome: Direct, unequivocal evidence for the new, revised pathway of phytanic acid -oxidation in humans. Biochem. Biophys. Res. Comm. 229, 205210.[ISI][Medline]
Kaufman, L. M. (1998). A syndrome of retinitis pigmentosa, congenital ichthyosis, hypergonadotropic hypogonadism, small stature, mental retardation, cranial dysmorphism, and abnormal electroencephalogram. Ophthalmic. Genet. 19, 6979.[ISI][Medline]
Kitareewan, S., Burka, L. T., Tomer, K. B., Parker, C. E., Deterding, L. J., Stevens, R. D., Forman, B. M., Mais, D. E., Heyman, R. A., McMorris, T., and Weinberger, C. (1996). Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR. Mol. Biol. Cell 7, 11531166.[Abstract]
Klenk, E., and Kremer, G. J. (1965). [Studies on the metabolism of phytol, dihydrophytol and phytanic acid]. Hoppe Seylers Z. Physiol. Chem. 343, 3951.[ISI][Medline]
Lemotte, P. K., Keidel, S., and Apfel, C. M. (1996). Phytanic acid is a retinoid X receptor ligand. Eur. J. Biochem. 236, 328333.[Abstract]
Levin, A. A., Sturzenbecker, L. J., Kazmer, S., Bosakowski, T., Huselton, C., Allenby, G., Speck, J., Kratzeisen, C., Rosenberger, M., Lovey, A., et al. (1992). 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR . Nature 355, 359361.[ISI][Medline]
Lohnes, D., Mark, M., Mendelsohn, C., Dolle, P., Decimo, D., LeMeur, M., Dierich, A., Gorry, P., and Chambon, P. (1995). Developmental roles of the retinoic acid receptors. J. Steroid Biochem. Mol. Biol. 53, 475486.[ISI][Medline]
Maden, M. (1994). Vitamin A in embryonic development. Nutr. Rev. 52, S3S12.[ISI][Medline]
Mangelsdorf, D. J., Umesono, K., and Evans, R. M. (1994). The retinoid receptors. In The Retinoids Biology Chemistry and Medicine (M. B. Sporn, A. B. Roberts, and D. S. Goodman, Eds.), pp. 319349. Raven Press, New York.
Minucci, S., Leid, M., Toyama, R., Saint-Jeannet, J., Peterson, V. J., Horn, V., Ishmael, J. E., Bhattacharyya, N., Dey, A., Dawid, I. B., and Ozato, K. (1997). Retinoid X receptor (RXR) within the RXR-retinoic acid receptor heterodimer binds its ligand and enhances retinoid-dependent gene expression. Mol. Cell. Biol. 17, 644655.[Abstract]
Mize, C. E., Avigan, J., Baxter, J. H., Fales, H. M., and Steinberg, D. (1966). Metabolism of phytol-U-14C and phytanic acid-U-14C in the rat. J. Lipid Res. 7, 692697.
Muralidharan, F. N., and Muralidharan, V. B. (1985). In vitro conversion of phytol to phytanic acid in rat liver: Subcellular distribution of activity and chemical characterization of intermediates using a new bromination technique. Biochim. Biophys. Acta 835, 3640.[ISI][Medline]
Muralidharan, F. N., and Muralidharan, V. B. (1986). Characterization of phytol-phytanate conversion activity in rat liver. Biochim. Biophys. Acta 883, 5462.[ISI][Medline]
Muralidharan, V. B., and Kishimoto, Y. (1984). Phytanic acid -oxidation in rat liver. Requirement of cytosolic factor. J. Biol. Chem. 259, 1302113026.
Napoli, J. L. (1996). Retinoic acid biosynthesis and metabolism. FASEB J. 10, 9931001.
Nau, H., Chahoud, I., Dencker, L., Lammer, E. J., and Scott, W. J. (1994). Teratogenicity of vitamin A and retinoids. In Vitamin A in Health and Disease (R. Blomhoff, Ed.), pp. 615664. Marcel Dekker, New York.
Nau, H., and Elmazar, M. M. (1999). Retinoid receptors, their ligands, and teratogenesis: Synergy and specificity of effects. In Handbook of Experimental Pharmacology, Vol. 139: Retinoids. The Biochemical and Molecular Basis of Vitamin A and Retinoid Action (H. Nau and W. S. Blaner, Eds.), pp. 465487. Springer, Berlin, Germany.
Pahan, K., Gulati, S., and Singh, I. (1994). Phytanic acid -oxidation in rat liver mitochondria. Biochim. Biophys. Acta 1201, 491497.[ISI][Medline]
Pahan, K., and Singh, I. (1993). Intraorganellar localization of CoASH-independent phytanic acid oxidation in human liver peroxisomes. FEBS Lett. 333, 154158.[ISI][Medline]
Posch, K. C., Boerman, M. H., Burns, R. D., and Napoli, J. L. (1991). Holocellular retinol binding protein as a substrate for microsomal retinal synthesis. Biochemistry 30, 62246230.[ISI][Medline]
Roberts, A. B., Lamb, L. C., and Sporn, M. B. (1980). Metabolism of all-trans-retinoic acid in hamster liver microsomes: Oxidation of 4-hydroxy- to 4-keto-retinoic acid. Arch. Biochem. Biophys. 199, 374383.[ISI][Medline]
Roberts, A. B., Nichols, M. D., Newton, D. L., and Sporn, M. B. (1979). In vitro metabolism of retinoic acid in hamster intestine and liver. J. Biol. Chem. 254, 62966302.[ISI][Medline]
Roberts, E. S., Vaz, A. D., and Coon, M. J. (1992). Role of isozymes of rabbit microsomal cytochrome P-450 in the metabolism of retinoic acid, retinol, and retinal. Mol. Pharmacol. 41, 427433.[Abstract]
Roy, B., Taneja, R., and Chambon, P. (1995). Synergistic activation of retinoic acid (RA)-responsive genes and induction of embryonal carcinoma cell differentiation by an RA receptor (RAR
)-, RAR ß-, or RAR
-selective ligand in combination with a retinoid X receptor-specific ligand. Mol. Cell. Biol. 15, 64816487.[Abstract]
Ruberte, E., Dolle, P., Chambon, P., and Morriss-Kay, G. (1991). Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos. Development 111, 4560.[Abstract]
Ruberte, E., Friederich, V., Chambon, P., and Morriss-Kay, G. (1993). Retinoic acid receptors and cellular retinoid binding proteins. III. Their differential transcript distribution during mouse nervous system development. Development 118, 267282.
Sass, J. O., Tzimas, G., and Nau, H. (1994). 9-cis-retinoyl-ß-D-glucuronide is a major metabolite of 9-cis-retinoic acid. Life Sci. 54, PL69PL74.
Scott, W. J., Jr., Walter, R., Tzimas, G., Sass, J. O., Nau, H., and Collins, M. D. (1994). Endogenous status of retinoids and their cytosolic binding proteins in limb buds of chick vs mouse embryos. Dev. Biol. 165, 397409.[ISI][Medline]
Singh, I., Pahan, K., Dhaunsi, G. S., Lazo, O., and Ozand, P. (1993). Phytanic acid -oxidation. Differential subcellular localization in rat and human tissues and its inhibition by nycodenz. J. Biol. Chem. 268, 99729979.
Steinberg, D. (1995). Refsum disease. In The Metabolic and Molecular Bases of Inherited Disease (C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, Eds.), pp. 23512369. McGraw-Hill, New York.
Steinberg, D., Avigan, J., Mize, C. E., Baxter, J. H., Cammermeyer, J., Fales, H. M., and Highet, P. F. (1966). Effects of dietary phytol and phytanic acid in animals. J. Lipid Res. 7, 684691.
Stoffel, W., and Kahlke, W. (1965). The transformation of phytol into 3,5,11,15-tetra-methylhexadecanoic (phytanic) acid in heredopathia atactica polyneuritiformis (Refsum's syndrome). Biochem. Biophys. Res. Comm. 19, 33.[ISI]
Stüttgen, G. (1982). Historical perspectives of tretinoin. J. Am. Acad. Dermatol. 15, 735740.
Suzuki, T., Ezure, T., and Ishida, M. (1998). Synergistic effects of some pairs of antioxidants and related agents on mouse leukaemia L5178Y cell growth in-vitro. J. Pharm. Pharmacol. 50, 11731177.[ISI][Medline]
Thaller, C., and Eichele, G. (1987). Identification and spatial distribution of retinoids in the developing chick limb bud. Nature 327, 625628.[ISI][Medline]
Tzimas, G., Sass, J. O., Wittfoht, W., Elmazar, M. M., Ehlers, K., and Nau, H. (1994). Identification of 9,13-dicis-retinoic acid as a major plasma metabolite of 9-cis-retinoic acid and limited transfer of 9-cis-retinoic acid and 9,13-dicis-retinoic acid to the mouse and rat embryos. Drug Metab. Dispos. 22, 928936.[Abstract]
Tzimas, G., Thiel, R., Chahoud, I., and Nau, H. (1997). The area under the concentration-time curve of all-trans-retinoic acid is the most suitable pharmacokinetic correlate to the embryotoxicity of this retinoid in the rat. Toxicol. Appl. Pharmacol. 143, 436444.[ISI][Medline]
Van Soest, S., Westerveld, A., de Jong, P. T., Bleeker-Wagemakers, E. M., and Bergen, A. A. (1999). Retinitis pigmentosa: Defined from a molecular point of view. Surv. Ophthalmol. 43, 321334.[ISI][Medline]
Verhoeven, N. M., Wanders, R. J., Poll-The, B. T., Saudubray, J. M., and Jakobs, C. (1998). The metabolism of phytanic acid and pristanic acid in man: A review. J. Inherit. Metab. Dis. 21, 697728.[ISI][Medline]
Verhoeven, N. M., Wanders, R. J., Schor, D. S., Jansen, G. A., and Jakobs, C. (1997). Phytanic acid -oxidation: Decarboxylation of 2-hydroxyphytanoyl-CoA to pristanic acid in human liver. J. Lipid Res. 38, 20622070.[Abstract]
Wanders, R. J., van Roermund, C. W., Schor, D. S., ten Brink, H. J., and Jakobs, C. (1994). 2-Hydroxyphytanic acid oxidase activity in rat and human liver and its deficiency in the Zellweger syndrome. Biochim. Biophys. Acta 1227, 177182.[ISI][Medline]
Wolfrum, C., Ellinghaus, P., Fobker, M., Seedorf, U., Assmann, G., Borchers, T., and Spener, F. (1999). Phytanic acid is ligand and transcriptional activator of murine liver fatty acid binding protein. J. Lipid Res. 40, 708714.
Yamagata, T., Momoi, M. Y., Yanagisawa, M., Kumagai, H., Yamakado, M., and Momoi, T. (1994). Changes of the expression and distribution of retinoic acid receptors during neurogenesis in mouse embryos. Brain Res. Dev. Brain Res. 77, 163176.[ISI][Medline]
Zhang, X.-K., and Pfahl, M. (1993). Hetero- and homodimeric receptors in thyroid and vitamin A action. Receptor 3, 183191.[ISI][Medline]
Zomer, A. W. M., Jansen, G. A., van der Burg, B., Verhoeven, N. M., Jakobs, C., Van Der Saag, P. T., Wanders, R. J., and Poll-The, B. T. (2000) Phytanoyl-CoA hydroxylase activity is induced by phytanic acid. Eur. J. Biochem. 267, 40634067.