Analysis of high dysmorphogenic activity of Ro 13-6307, a tetramethylated tetralin analog of retinoic acid.
Certain synthetic retinoids differ widely from retinoic acid (RA) in teratogenic potency, being much more or much less effective than RA. It is assumed that the potency of a retinoid may depend on the nature of its interaction with cellular binding components (nuclear retinoic acid receptors or cytoplasmic binding proteins) and, as in the case of retinoids that are mammalian teratogens, on factors that determine its accessibility to the embryo. To investigate some of the factors that contribute to potency, we used a new synthetic retinoid Ro 13-6307 that differs in structure from RA in having an aromatic ring inserted in its side chain along with gem dimethyl modification of the natural cyclohexenyl ring. Pregnant ICR mice were given a single oral dose (0, 1, or 10 mg/kg) on day 11 of gestation, and the resultant teratogenic outcome was monitored on day 17. Direct effects on cell differentiation were obtained by exposing high density cultures of limb bud mesenchymal cells to a range of concentrations (0.3 ng/ml-3 micrograms/ml) of Ro 13-6307 and scoring for chondrogenic suppression. Concentrations reaching the embryo after maternal administration of Ro 13-6307 were measured by HPLC to quantify the analog for a period of 4 h after administration of the oral dose. We found that this retinoid was 40-fold as active as RA in both inducing teratogenesis and suppressing chondrogenesis, yet its concentration in the affected embryo was only a fraction of that achieved after an equivalent dose of RA was employed in a similar protocol.(ABSTRACT TRUNCATED AT 250 WORDS)
Kochhar
D M
DM
Department of Anatomy, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Penner
J D
JD
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005231:Fatty Acids, Unsaturated; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects*; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D013723:Teratogens / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*
D005231:Fatty Acids, Unsaturated; D013723:Teratogens; D014212:Tretinoin; C077135:Ro 13-6307