4-Methylpyrazole partially ameliorated the teratogenicity of retinol and reduced the metabolic formation of all-trans-retinoic acid in the mouse.
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.
Collins
M D
MD
Institut für Toxikologie and Embryonalpharmakologie, Freie Universität Berlin, Federal Republic of Germany.
Eckhoff
C
C
Chahoud
I
I
Bochert
G
G
Nau
H
H
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003864:Depression, Chemical; D005260:Female; D000077604:Fomepizole; D008297:Male; D051379:Mice; D011247:Pregnancy; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism; D013723:Teratogens / Q000633:toxicity*; D014212:Tretinoin / Q000378:metabolism*; D014801:Vitamin A / Q000037:antagonists & inhibitors* / Q000633:toxicity
D011720:Pyrazoles; D013723:Teratogens; D014801:Vitamin A; D014212:Tretinoin; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase