title: Structure-activity relationships of retinoids in developmental toxicology. III. Contribution of the vitamin A beta-cyclogeranylidene ring.
abstract: The teratogenic potency of congeners of all-trans-retinoic acid (all-trans-RA) containing modifications or substitution of the naturally occurring beta-cyclogeranylidene ring was determined in Golden hamsters and compared to that of all-trans-RA. The following ring-modified retinoids were screened: phenyl (Ro 8-8717), furyl (Ro 8-9750), 4-methoxy-2,3,6-trimethylphenyl (Ro 21-6667), which also has a thiomethylene group in place of the trans-8,9 double bond of the etretin side chain, 4-hydroxy-2,3,6-trimethylphenyl (Ro 11-4768), 2-chloro-3,6-dimethyl-4-methoxyphenyl (Ro 12-0995), 2-(1-methoxyethyl)-5,5-dimethyl-1-cyclopentenyl (Ro 10-1770), 2-acetyl-5,5-dimethyl-1-cyclopentenyl (Ro 8-7699), and 10,11-epoxy-11,11-dimethyl (juvenile hormone III), which also has the bonds corresponding to the 7,8- and 11,12-double bond of the retinoid skeleton saturated. The retinoids Ro 12-4824, Ro 12-4825, and SRI2712-24 had C4-keto, C18-hydroxyl, and C18-methyl substituents, respectively. Motretinid (Ro 11-1430) had both 4-methoxy-2,3,6-trimethylphenyl ring and ethyl amide polar group modifications. Single oral retinoid doses administered to pregnant dams at 10:00 AM on Day 8 neither induced signs of hypervitaminosis A nor induced weight loss in any of the treated groups. Teratogenically active retinoids induced a malformation syndrome identical to that induced by all-trans-RA. At retinoid doses that were associated with malformations in all of the fetuses, embryolethality remained near that of vehicle-treated controls. The phenyl retinoid Ro 8-8717 was embryolethal but was not teratogenic. The ethyl amide derivative of the human and animal teratogen etretinate, motretinid, was teratogenic only at the highest dose administered, 350 mg/kg. The retinoids Ro 12-4824, Ro 12-4825, Ro 8-7699, and SRI 2712-24 were as potent as all-trans-RA. The chlorine substituted retinoid, Ro 12-0995, was sixfold more teratogenic than all-trans-RA, and the cyclopentene retinoid, Ro 10-1770, was 19 times more potent than all-trans-RA. The retinoids with furyl or epoxy group substitution for the cyclohexenyl ring were devoid of teratogenic activity up to equimolar doses of 75 mg/kg of all-trans-RA, and Ro 21-6667 was teratogenically inactive at a dose equivalent to 150 mg/kg of all-trans-RA. Major modifications of the beta-cyclogeranylidene ring can be made without altering teratogenic activity.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Center for Environmental Toxicology, Utah State University, Logan 84322.
authors.forename: W B
authors.initials: WB
authors.lastname: Howard
authors.forename: C C
authors.initials: CC
authors.lastname: Willhite
authors.forename: M I
authors.initials: MI
authors.lastname: Dawson
authors.forename: R P
authors.initials: RP
authors.lastname: Sharma
mesh_terms: D000818:Animals; D006224:Cricetinae; D003510:Cyclohexanes / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D007605:Juvenile Hormones / Q000633:toxicity; D007928:Lethal Dose 50; D008647:Mesocricetus; D011247:Pregnancy; D012176:Retinoids / Q000633:toxicity*; D012717:Sesquiterpenes / Q000633:toxicity; D013329:Structure-Activity Relationship; D013723:Teratogens; D014801:Vitamin A / Q000633:toxicity*
chemical_list: D003510:Cyclohexanes; D007605:Juvenile Hormones; D012176:Retinoids; D012717:Sesquiterpenes; D013723:Teratogens; D014801:Vitamin A; C036585:juvenile hormone III