Transplacental pharmacokinetics and teratogenicity of a single dose of retinol (vitamin A) during organogenesis in the mouse

Eckhoff, Christian; Löfberg, Boel; Chahoud, Ibrahim; Bochert, Gerd; Nau, Heinz

doi:10.1016/0378-4274(89)90172-0

Cited by 52 publications

(18 citation statements)

References 18 publications

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“…dose of retinol, despite the fact that the AUC of all-trans RA is quite different in the two instances (Creech Eckhoff et al 1989). The AUC of all-trans RA was approximately a factor of eight higher when the mice were dosed with 10 mg/kg of all-trans RA, than when the mice received 100 mg/kg retinol.…”

Section: Discussionmentioning

confidence: 90%

“…Similar to the forelimb and hindlimb anomalies categories, the group administered 4-MP and retinol had significantly more defects (Z 2, 1 df p _<0.01) than untreated controls. All three of the specific defects listed in this category were significantly (~2, 1 df, p _<0.01) decreased by 4-MP pretreatment Eckhoff et al 1989). For primary straight-chain alcohols, it has been demonstrated that 8 and 16 carbon alcohols were oxidized more efficiently than ethanol by class I alcohol dehydrogenase isozymes (Burnell and Boston 1989) which are inhibitable by ethanol for the oxidation of retinol (Mezey and Holt 1971).…”

Section: Discussionmentioning

confidence: 94%

“…Previous studies have suggested that the embryotoxic sequelae result from the biotransformation of retinol to all-trans RA Eckhoff et al 1989), although it is difficult to attribute the teratogenicity of retinol to a single metabolic product because there are a number of retin01 metabolites in addition to the parent compound (e.g., Eckhoff et al 1990). There is evidence that all-trans-RA can be synthesized from retinol by several different enzymatic systems.…”

Section: Discussionmentioning

confidence: 99%

“…Little is known about the regulation of endogenous blood and tissue concentrations of all-trans-RA and how vitamin A intake influences such levels. In an attempt to determine the proximate teratogen(s) of high doses of preformed vitamin A, two reports have tried to determine if significant embryonic exposures t0 all-trans-RA occur after mice were administered a teratogenic dose of retinol Eckhoff et al 1989). Although high concentrations of all-trans-RA and other RA metabolites were found as products of retinol metabolism in maternal plasma and embryo, it remained unclear whether the teratogenic activity of vitamin A was exclusively attributable to a metabolic oxidation of retinol to RA metabolites.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 1992

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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.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 1992

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“…Recent experiments have shown that teratogenic doses of retinol (100-200 mg/kg) in the mouse were accompanied by very high concentrations of retinoic acid compounds, particularly of the potent teratogen all-trans-retinoic acid (all-trans-RA), in maternal plasma and embryonic tissues (Kochhar et al 1988;Eckhoff et al 1989).…”

Section: Introductionmentioning

confidence: 99%

Vitamin A supplementation increases levels of retinoic acid compounds in human plasma: possible implications for teratogenesis

Eckhoff

Nau

1990

Arch Toxicol

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The concentrations of retinoic acid compounds were monitored by a newly developed highly sensitive HPLC procedure in plasma of six volunteers who received 833 IU vitamin A per kg body weight per day during a 20-day period. There was a significant increase of all-trans-retinoic acid (two-fold), 13-cis-retinoic acid (7-fold) and 13-cis-4-oxoretinoic acid (5-fold) over endogenous plasma levels of these retinoids. The same compounds had previously been found after treatment with the teratogenic drug isotretinoin (Roaccutan, Accutane). Our results raise the possibility that high vitamin A intake may carry a teratogenic risk attributable to increased levels of retinoic acid compounds generated from retinol by metabolic processes.

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Clinical teratology counseling and consultation report: High dose β-carotene use during early pregnancy

et al. 1996

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Transplacental pharmacokinetics and teratogenicity of a single dose of retinol (vitamin A) during organogenesis in the mouse

Cited by 52 publications

References 18 publications

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

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

Vitamin A supplementation increases levels of retinoic acid compounds in human plasma: possible implications for teratogenesis

Clinical teratology counseling and consultation report: High dose β-carotene use during early pregnancy

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