HPLC-MS/MS analysis of the products generated from all-trans-retinoic acid using recombinant human CYP26A

Chithalen, James V.; Luu, Luong; Petkovich, Martin; Jones, Glenville

doi:10.1194/jlr.m100343-jlr200

Cited by 72 publications

(57 citation statements)

References 35 publications

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“…The use of MS to analyze polar retinoids and REs has been reported (53,54,76,77). Our data confirmed that LDI-MS is a suitable approach to detect retinoids, especially REs, in biological samples.…”

Section: Characterization Of Novel Res Using Mass Spectrometrysupporting

confidence: 74%

Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid

Tang

Suh

et al. 2007

Journal of Lipid Research

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We investigated the effects of two natural dietary retinoid X receptor (RXR) ligands, phytanic acid (PA) and docosahexaenoic acid (DHA), on proliferation and on the metabolism of retinol (vitamin A) in both cultured normal human prostate epithelial cells (PrECs) and PC-3 prostate carcinoma cells. PA and DHA inhibited the proliferation of the parental PC-3 cells and PC-3 cells engineered to overexpress human lecithin:retinol acyltransferase (LRAT) in both the absence and presence of retinol. A synthetic RXR-specific ligand also inhibited PC-3 cell proliferation, whereas all-trans retinoic acid (ATRA) did not. PA and DHA treatment increased the levels of retinyl esters (REs) in both PrECs and PC-3 cells and generated novel REs that eluted on reverse-phase HPLC at 54.0 and 50.5 min, respectively. Mass spectrometric analyses demonstrated that these novel REs were retinyl phytanate (54.0 min) and retinyl docosahexaenoate (50.5 min). Neither PA nor DHA increased LRAT mRNA levels in these cells. In addition, we demonstrate that retinyl phytanate was generated by LRAT in the presence of PA and retinol; however, retinyl docosahexaenoate was produced by another enzyme in the presence of DHA and retinol. Vitamin A (retinol) and its natural metabolites and synthetic derivatives, known as retinoids, play important roles in regulating cell proliferation, differentiation, and embryonic development (1-3). The physiological activities of retinoids are primarily carried out via nuclear receptors that transcriptionally activate certain retinoid-responsive genes. Two types of retinoid receptors have been identified, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each with three subtypes, a, b, and g (4-6). RAR/RXR heterodimers bind to specific DNA sequences known as retinoic acid response elements (7). Ligand binding of RARs and RXRs regulates the transcription of retinoic acid-responsive genes. The actions of RARs and RXRs on gene transcription also require a highly coordinated interaction with a large number of coactivators and corepressors (8).The appropriate intracellular retinoid concentrations are maintained by the activities of several metabolic enzymes (9-11). All-trans retinol (ROH; vitamin A) is the precursor of other natural retinoids. Retinol dehydrogenases oxidize ROH to all-trans retinaldehyde, and then all-trans retinaldehyde is further metabolized to all-trans retinoic acid (ATRA) by retinaldehyde dehydrogenases (11). Currently, four members of the retinaldehyde dehydrogenase family have been identified, retinaldehyde dehydrogenases 1, 2, 3, and 4 (12). ROH is converted to all-trans retinyl esters primarily by lecithin:retinol acyltransferase (LRAT), and retinyl esters (REs) are hydrolyzed to retinol by ester hydrolases (9,(13)(14)(15). REs are regarded as the storage forms of retinol (9). ATRA is oxidized to more polar metabolites, such as 4-oxo-retinoic acid, by a cytochrome P450 family member (CYP26) (16)(17)(18)(19).Retinoids are required for the appropriate differentiation of normal ro...

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Section: Characterization Of Novel Res Using Mass Spectrometrysupporting

confidence: 74%

Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid

Tang

Suh

et al. 2007

Journal of Lipid Research

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“…7 RA is further oxidized to more polar metabolites by cytochrome P450 family members such as CYP26A1. 31 RDH9 converts 9-cis-retinol into 9-cis-retinal, has the highest efficiency (V m /K m ) among RHDs. Interestingly, when we induced RDH9 expression in kidney of Tg26 mice, RDH1 expression was also significantly increased.…”

Section: Discussionmentioning

confidence: 99%

Induction of Retinol Dehydrogenase 9 Expression in Podocytes Attenuates Kidney Injury

Dai

Chuang

et al. 2014

Journal of the American Society of Nephrology

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The intracellular concentration of retinoic acid is determined by two sequential oxidation reactions that convert retinol to retinoic acid. We recently demonstrated that retinoic acid synthesis is significantly impaired in glomeruli of HIV-1 transgenic mice (Tg26), a murine model of HIV-associated nephropathy. This impaired retinoic acid synthesis correlates with reduced renal expression of retinol dehydrogenase 9, which catalyzes the rate-limiting step of retinoic acid synthesis by converting retinol to retinal. Because retinoic acid has renal protective effects and can induce podocyte differentiation, we hypothesized that restoration of retinoic acid synthesis could slow the progression of renal disease. Herein, we demonstrate that overexpression of retinol dehydrogenase 9 in cultured podocytes induces the expression of podocyte differentiation markers. Furthermore, we confirm that podocyte-specific overexpression of retinol dehydrogenase 9 in mice with established kidney disease due to either HIV-associated nephropathy or adriamycin-induced nephropathy decreases proteinuria, attenuates kidney injury, and restores podocyte differentiation markers. Our data suggest that restoration of retinoic acid synthesis could be a new approach to treat kidney disease.

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“…Enzymes of the cytochrome P450 26 subfamily (CYP26A1, CYP26B1 and CYP26C1) catalyze reactions that convert RA into more polar metabolites, primarily 4-hydroxy-RA, which can be further oxidized to 4-oxo-RA (e.g. Chithalen et al, 2002) (Fig. 2A).…”

Section: The Ra Degradation Pathwaymentioning

confidence: 99%

Retinoic acid signalling during development

2012

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Retinoic acid (RA) is a vitamin A-derived, non-peptidic, small lipophilic molecule that acts as ligand for nuclear RA receptors (RARs), converting them from transcriptional repressors to activators. The distribution and levels of RA in embryonic tissues are tightly controlled by regulated synthesis through the action of specific retinol and retinaldehyde dehydrogenases and by degradation via specific cytochrome P450s (CYP26s). Recent studies indicate that RA action involves an interplay between diffusion (morphogen-like) gradients and the establishment of signalling boundaries due to RA metabolism, thereby allowing RA to finely control the differentiation and patterning of various stem/progenitor cell populations. Here, we provide an overview of the RA biosynthesis, degradation and signalling pathways and review the main functions of this molecule during embryogenesis.

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HPLC-MS/MS analysis of the products generated from all-trans-retinoic acid using recombinant human CYP26A

Cited by 72 publications

References 35 publications

Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid

Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid

Induction of Retinol Dehydrogenase 9 Expression in Podocytes Attenuates Kidney Injury

Retinoic acid signalling during development

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