Structure-activity relationships of retinoids in developmental toxicology. II. Influence of the polyene chain of the vitamin A molecule.
The comparative teratogenic potencies of 7,8-dihydroretinoic acid, 7,8-dehydroretinoic acid, 9,10-dihydroretinoic acid, 9-cis-retinal, hydroxenin, oxenin, the C15 analog of all-trans-retinoic acid, abscissic acid, beta-C14 aldehyde, beta-ionone, and psuedoionone were determined in golden Syrian hamsters and compared with that of all-trans-retinoic acid. A single oral dose of each retinoid on Day 8 of gestation failed to induce signs of retinoid intoxication in the dams and the maternal weight gain was not affected significantly, except after treatment with beta-C14 aldehyde, pseudoionone, and the lowest dose of 9-cis-retinal, where maternal weight was depressed. A significant teratogenic response was observed after intubation of 7,8-dihydroretinoic acid, 7,8-dehydroretinoic acid, or 9-cis-retinal. The highest dose of hydroxenin (equivalent to nearly seven times an equimolar teratogenic dose of all-trans-retinoic acid) showed a limited teratogenic response. None of the remaining retinoids induced terata. The results suggest that the side chain plays an important role in retinoid embryotoxicity and that even minor structural alterations of retinoids at the side chain can abolish teratogenic activity. The present results indicate that a polyene chain of greater than five carbon atoms was necessary for retinoid teratogenic activity and that the presence of the ring, the nine-carbon side chain, and the acidic polar terminus was insufficient to ensure teratogenic activity. Retinoid teratogenicity in hamsters required the hydrophobic ring, a terminal polar group with an acidic pKa, and the hydrophobic, curved plane of the tetraene chain.
Willhite
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D000818:Animals; D001835:Body Weight / Q000187:drug effects; D006224:Cricetinae; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D008647:Mesocricetus; D011090:Polyenes / Q000633:toxicity*; D011247:Pregnancy; D012176:Retinoids / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013723:Teratogens
D011090:Polyenes; D012176:Retinoids; D013723:Teratogens