Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands

Abstract

Previous studies in our laboratory identified retinoid-induced defects that are mediated by RAR-RXR heterodimerization using interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in mice (Elmazar et al. 1997, Toxicol Appl Pharmacol 146:21-28; Elmazar et al. 2001, Toxicol Appl Pharmacol 170:2-9; Nau and Elmazar 1999, Handbook of experimental pharmacology, vol 139, Retinoids, Springer-Verlag, pp 465-487). The present study was designed to investigate whether these RAR-RXR heterodimer-mediated defects can be also induced by interactions of natural and synthetic ligands for retinoid receptors. A non-teratogenic dose of the natural RXR agonist phytanic acid (100 mg/kg orally) or its precursor phytol (500 mg/kg orally) was coadministered with a synthetic RARalpha-agonist (Am580; 5 mg/kg orally) to NMRI mice on day 8.25 of gestation (GD8.25). Furthermore, a non-teratogenic dose of the synthetic RXR agonist LGD1069 (20 mg/kg orally) was also coadministered with the natural RAR agonist, all- trans-retinoic acid (atRA, 20 mg/kg orally) or its precursor retinol (ROH, 50 mg/kg orally) to NMRI mice on GD8.25. The teratogenic outcome was scored in day-18 fetuses. The incidence of Am580-induced resorptions, spina bifida aperta, micrognathia, anotia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, short and absent tail, fused ribs and fetal weight retardation were potentiated by coadministration of phytanic acid or its precursor phytol. Am580-induced exencephaly and cleft palate, which were not potentiated by coadministration with the synthetic RXR agonists, were also not potentiated by coadministration with either phytanic acid or its precursor phytol. LGD1069 potentiated atRA- and ROH-induced resorption, exencephaly, spina bifida, aperta, ear anotia and microtia, macroglossia, kidney hypoplasia, undescended testis, atresia ani, tail defects and fetal weight retardation, but not cleft palate. These results suggest that synergistic teratogenesis can be induced by coadministration of a natural RXR ligand (phytanic acid) with a synthetic RAR agonist (Am580). Thus, certain potentially useful therapeutic agents or nutritional factors such as phytanic acid should be tested for teratogenic risk by coadministration with other retinoid receptor agonists.

HDAC2 phosphorylation-dependent Klf5 deacetylation and RARα acetylation induced by RAR agonist switch the transcription regulatory programs of p21 in VSMCs

“…However, their therapeutic use has been precluded by serious adverse effects such as skin or liver toxicity and teratogenesis because RARs are widely expressed in various tissues [53]. To further uncover the possible other mechanism for Am80-induced growth inhibition, gene profiling experiment was performed after treatment with or without Am80.…”

Phytol/Phytanic Acid and Insulin Resistance: Potential Role of Phytanic Acid Proven by Docking Simulation and Modulation of Biochemical Alterations

“…Phytol, therefore, is a precursor of the natural rexinoid phytanic acid that, besides triggering RXR, it activates the full spectrum of PPARs [14]. It also boosts the transcriptional activity of the PPAR/RXR heterodimers [3] and other nuclear receptors, viz., retinoic acid receptor (RAR) [15] where phytol and its metabolite, potentiate the teratogenic effects induced by a synthetic RARα agonist in mice.…”

Phytol in a pharma-medico-stance

“…[60], antitumor in hepatocellular carcinoma cells [21] while PA by anti-teratogenic (100 mg/kg; p.o.) [7,59,61] and anti-mammary (with a vitamin D analog) cancer activities [60] in mice. There is also evidence of prostate cancer due to elevated levels of PA [62e65], but the later conclusion is a bit controversial [64,66e68].…”

“…Physic-chemical properties of phytol [2,188] PYT as hair facilitator, hair fall defense, antidandruff and antiinfectives [146,148,149] Phytol sources [22e31] PYT in cardiac complications [107,123e132] Synthesis of PYT [29,32e35] PYT in nephro-and hepatoxicities [116,118,190,191] Metabolism of PYT [31,36,41e48] PYT as a source of formic acid [192e194] Antioxidant activity of PYT [16,19,95] PYT degredation product as peroxisomal disorders in child and adults [98,99,102,104,109e113] Anti-inflammatory activity of PYT [97] PYT in RD [100e104,110e113] Antimicrobial and antiprotozoal activities of PYT [8,13,14,16,20,50,53] PYT in neonatal adrenoleucodystrophy [102,104,110e112] Cytotoxic activity of PYT [17] PYT in cerebra-hepato-renal (Zellweger) syndrome [108] PYT as anticancer/antitumor agent [21,54e57,60,62e68] PYT in RZCP [105] Antimutagenic activity of PYT [58] PYT in ataxia [109] Antiteratogenic activity of PYT [7,59,61] PYT in lupus nephritis [195] PYT as immunoadjuvant [12,69e79] PYT in SLS [40,102] Antidiabetic properties of PYT [11,40,61,80e87] PYT in sexual problems [50] PYT as lipid lowering agent [6,44,82,88e94] PYT in mitochondrial respiration and homeostasis <...>…”