Enzymatic catalysis of the oxidations of ethanol, all-trans-retinol (tretinol) and all-trans-retinal (t-retinal) were demonstrated in the cytosolic fractions of rat conceptal homogenates at day 12 of gestation. Products of the retinoid oxidation reactions were identified with HPLC by comparing elution times with those of authentic standard retinoids. NAD-dependent oxidations of each of the three substrates were demonstrable with assay conditions used; t-retinol and t-retinal each were converted to readily detectable quantities of all-trans-retinoic acid (t-RA). At 1.0 mM or higher concentrations, ethanol effectively inhibited the synthesis of t-RA from both t-retinol and t-retinal when adult hepatic cytosol was used as enzyme source. Approximately 70% and 40% inhibitions, respectively, were observed at 10 mM ethanol concentrations. By contrast, for the reactions catalyzed by rat conceptal cytosol (RCC) under the same experimental conditions, ethanol falled to inhibit significantly the conversion of either t-retinol or t-retinal to t-RA at concentrations up to 1,000 mM. For the RCC-catalyzed conversion of t-retinal to t-RA, increasing concentrations of ethanol (0 to 1.0 M) resulted in linear increases rather than decreases in quantities of t-RA generated. At a 2.0 M concentration of ethanol, the quantity of t-RA increased by > 50%. Significant inhibition of t-RA generation from t-retinal occurred only at extremely high (> 4.0 M) concentrations. The results indicated that ethanol was a very ineffective inhibitor of RCC-catalyzed synthesis of t-RA from either t-retinol or t-retinal. This contrasted strongly with effective inhibitory effects with adult hepatic cytosol as enzyme source. The results supported the concept that competitive inhibition of conversion of t-retinol to t-RA in conceptal tissues is not a significant factor in ethanol-elicited embryotoxicity and dysmorphogenesis, at least in rodents. Mechanisms for the ethanol-induced increases in conversion of t-retinal to t-RA remain to be elucidated.
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http://dx.doi.org/10.1111/j.1530-0277.1996.tb05275.x | DOI Listing |
Alcohol Clin Exp Res
August 1996
Department of Pharmacology, School of Medicine, University of Washington, Seattle 98195, USA.
Enzymatic catalysis of the oxidations of ethanol, all-trans-retinol (tretinol) and all-trans-retinal (t-retinal) were demonstrated in the cytosolic fractions of rat conceptal homogenates at day 12 of gestation. Products of the retinoid oxidation reactions were identified with HPLC by comparing elution times with those of authentic standard retinoids. NAD-dependent oxidations of each of the three substrates were demonstrable with assay conditions used; t-retinol and t-retinal each were converted to readily detectable quantities of all-trans-retinoic acid (t-RA).
View Article and Find Full Text PDFTeratology
July 1996
Department of Pharmacology, School of Medicine, University of Washington, Seattle 98165, USA.
Whole rat conceptuses (10.5 gestational days) were explanted into a culture medium containing all-trans-retinol (t-retinol, vitamin A1), ethanol, or combinations of the two alcohols at various concentrations, and were cultured at 37 degrees C for 24 hr. Parameters emphasized in morphological analyses were branchial arch development, closure of neural tube, axial rotation, and development of otic vesicles and of optic cup.
View Article and Find Full Text PDFDev Dyn
January 1996
Developmental Biology Research Centre, King's College London, United Kingdom.
Retinoic acid and its isoforms are considered to be endogenous compounds which regulate embryonic development. In the work reported here we have determined which retinoids are present in zebrafish embryos and how their levels change throughout development and into adulthood. All-trans-RA is present and its level does not change significantly during embryogenesis.
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