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

Arch Toxicol. 1992;66(9):652-9. doi: 10.1007/BF01981505.


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-time-curve (AUC) of metabolically generated all-trans retinoic acid in maternal plasma, and an 84% decrease in the embryonic AUC were observed when mice had been pretreated with the alcohol dehydrogenase inhibitor 4-methylpyrazole. A similar reduction was observed for the major metabolite of all-trans retinoic acid in the mouse, all-trans-4-oxoretinoic acid. However, 4-methylpyrazole pretreatment decreased the AUC of retinol by 10% in maternal plasma and 15% in embryo. Treatment with retinol alone resulted in 55.6%, 43.9% and 56.0% skeletal anomalies of the forelimbs, hindlimbs and craniofacial structures, respectively. Pretreatment with 4-methylpyrazole lowered the retinol induced skeletal defects to 31.3%, 24.0% and 31.3%, respectively, in the forelimb, hindlimb and craniofacial region. Typical retinoid-induced malformations for gestational day 11, e.g. bent or reduced zeugopod or stylopod elements, or cleft palate, were significantly reduced by 4-methylpyrazole pretreatment but were still detected in significantly higher prevalence than in control mice. These data suggest that the teratogenic activity of a single high dose of vitamin A in mouse is partially but not exclusively dependent on the metabolic activation of retinol to all-trans retinoic acid. Thus it could be hypothesized that retinol is either a proximate teratogen or a coteratogen with all-trans retinoic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Drug-Induced / pathology
  • Alcohol Dehydrogenase / antagonists & inhibitors
  • Alcohol Dehydrogenase / metabolism
  • Animals
  • Chromatography, High Pressure Liquid
  • Depression, Chemical
  • Female
  • Fomepizole
  • Male
  • Mice
  • Pregnancy
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology*
  • Stereoisomerism
  • Teratogens / toxicity*
  • Tretinoin / metabolism*
  • Vitamin A / antagonists & inhibitors*
  • Vitamin A / toxicity


  • Pyrazoles
  • Teratogens
  • Vitamin A
  • Tretinoin
  • Fomepizole
  • Alcohol Dehydrogenase