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

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Abstract

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 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.

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Author notes

  1. C. Eckhoff

    Present address: Hoffmann-LaRoche, Inc., 340 Kingsland Street, 07110-1199, Nutley, NJ, USA

Authors and Affiliations

  1. Institut für Toxikologie and Embryonalpharmakologie, Freie Universität Berlin, W-1000, Berlin 33, Federal Republic of Germany

    M. D. Collins, C. Eckhoff, I. Chahoud, G. Bochert & H. Nau

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  2. C. Eckhoff
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  3. I. Chahoud
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  4. G. Bochert
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Collins, M.D., Eckhoff, C., Chahoud, I. et al. 4-Methylpyrazole partially ameliorated the teratogenicity of retinol and reduced the metabolic formation of all-trans-retinoic acid in the mouse. Arch Toxicol 66, 652–659 (1992). https://doi.org/10.1007/BF01981505

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  • DOI: https://doi.org/10.1007/BF01981505

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