4-Methylpyrazole partially ameliorated the teratogenicity of retinol and reduced the metabolic formation of all-trans-retinoic acid in the mouse

  title={4-Methylpyrazole partially ameliorated the teratogenicity of retinol and reduced the metabolic formation of all-trans-retinoic acid in the mouse},
  author={Michael D. Collins and Christian Eckhoff and Ibrahim Chahoud and Gerd Bochert and Heinz Nau},
  journal={Archives of Toxicology},
Oral administration of retinol (50 mg/kg) to NMRI mice on day 11 of gestation (vaginal plug = day 0) led to the metabolic formation of high quantities of all-trans retinoic acid and all-trans-4-oxoretinoic acid, both known as potent teratogenic agents in the mouse. A 96% reduction of the area under the concentration-versus-timecurve (AUC) of metabolically generated alltrans retinoic acid in maternal plasma, and an 84% decrease in the embryonic AUC were observed when mice had been pretreated… 

The high sensitivity of the rabbit to the teratogenic effects of 13-cis-retinoic acid (isotretinoin) is a consequence of prolonged exposure of the embryo to 13-cis-retinoic acid and 13-cis-4-oxo-retinoic acid, and not of isomerization to all-trans-retinoic acid

The results suggest that the high sensitivity of the rabbit to the teratogenic effects of 13-cis-RA can be attributed mainly to the 13- cis-isomers and not to isomerization to all-trans-RA, and supports the view that embryonic AUC values should be considered as the most suitable pharmacokinetic correlate to retinoid induced teratogenesis.

Nutrient Metabolism Embryotoxic Doses of Vitamin A to Rabbits Result in Low Plasma but High Embryonic Concentrations of All-£rans-RetinoicAcid: Risk of Vitamin A Exposure in Humans1'2'3

A very markable finding of this study is the marginal increase of plasma concentrations of all-trans-RA over their en dogenous levels, which is comparable to the human situation after vitamin A intake.

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

Results suggest that synergistic teratogenesis can be induced by coadministration of a natural RXR ligand (phytanic acid) with a synthetic RAR agonist (Am580) and certain potentially useful therapeutic agents or nutritional factors such as phytanic acid should be tested for teratogenic risk by co administration with other retinoid receptor agonists.

Genetic Evidence That Retinaldehyde Dehydrogenase Raldh1 (Aldh1a1) Functions Downstream of Alcohol Dehydrogenase Adh1 in Metabolism of Retinol to Retinoic Acid*

It is demonstrated that Raldh1 functions downstream of Adh1 in the oxidative metabolism of excess retinol and that toxicity correlates primarily with accumulatingretinol rather than retinaldehyde.

Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation.

Findings suggest that opposing actions of CRBP1 and ADH1 enable a large fraction of liver retinol to remain esterified due toCRBP1 action, while continuously allowing some retinols to be oxidized to retinoic acid by ADH 1 for degradative retinoid turnover under any dietary vitamin A conditions.

Acute but not chronic ethanol exposure impairs retinol oxidation in the small and large intestine of the rat

  • A. ParlesakK. EllendtK. O. LindrosC. Bode
  • Medicine, Biology
    European journal of nutrition
  • 2005
Ethanol markedly inhibits in vitro cytosolic retinol oxidation in the small intestinal mucosa, which is considerably lower than that found in the colon, suggesting that this might contribute to the ethanol–induced increase in intestinal permeability.

Retinoid Concentrations in the Mouse during Postnatal Development and after Maternal Vitamin A Supplementation

The results show for the first time that supplementation with high doses of VA during the lactation period in mice can affect serum retinol concentrations in the neonates and report that day 7 after birth is a critical time in the tissue distribution of retinoids during postnatal development.

Automated solid-phase extraction and liquid chromatographic method for retinoid determination in biological samples.

  • R. RühlF. Schweigert
  • Chemistry, Medicine
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
  • 2003

13-cis retinoic acid inhibits development and progression of chronic allograft nephropathy.

Teratogenicity of the 13-cis and all-trans-isomers of the aromatic retinoid etretin: correlation to transplacental pharmacokinetics in mice during organogenesis after a single oral dose.

The results indicate that the low teratogenic potency of 13-cis-etretin is due to a limited placental transfer of this compound; on the other hand, the potent teratogen all-trans-et Retinoids is rapidly and extensively transferred to the embryo.

Teratogenicity of steady-state concentrations of etretinate and metabolite acitretin maintained in maternal plasma and embryo by intragastric infusion during organogenesis in the mouse: a possible model for the extended elimination phase in human therapy.

The results emphasize the high teratogenic risk of relatively low, persisting concentrations of etretinate and etretin such as those observed after discontinuation of human therapy, because the area of the concentration-time curve is likely to be the decisive parameter in regard to teratogenesis.

Terminal-group oxidation of retinol by mouse epidermis. Inhibition in vitro and in vivo.

The ability to inhibit the oxidation ofretinol to retinoic acid in mouse epidermis provides a potential method to resolve the roles of retinol and retinoIC acid in epithelial function.

The biosynthesis of retinoic acid from retinol by rat tissues in vitro.

Characterization of oxidized and glucuronidated metabolites of retinol in monkey plasma by thermospray liquid chromatography/mass spectrometry.

A major metabolic pathway of high-dose vitamin A in the non-human primate is apparently the oxidation of the primary alcohol group of retinol resulting in the formation of all-trans-retinoic acid.