Teratogenicity ofN‐(4‐hydroxyphenyl) ‐all‐trans‐retinamide in rats and rabbits

摘要

AbstractN‐(4‐hydroxyphenyl)‐all‐trans‐retinamide (HPR) has potential efficacy in the treatment of dermatologic, arthritic, and neoplastic disorders. The teratogenicity of such a compound is of special concern in light of the known adverse effects of retinoids, in general, on the developing conceptus. In these studies, Sprague‐Dawley rats and New Zealand White rabbits were treated orally from gestation days 6 to 15 and 6 to 18, respectively, with 0, 20, 125, or 800 mg/kg/day of HPR.In rat fetuses, low incidences of hydrocephaly (mid‐ and high‐dosage groups) were observed. Fetal tissue (ng/g) and maternal plasma (ng/ml) concentrations of HPR, its major metabolite (N‐[4‐methoxyphenyl] retinamide [MPR]) and retinol were determined in separate groups of similarly‐treated rats 3 h following the last dose on gestation day 15. Fetal tissue concentrations of HPR and MPR were approximately one‐half maternal plasma concentrations. A dose related reduction in maternal plasma and fetal tissue concentrations of retinol were also observed.In mid‐ and high‐dosage rabbit fetuses, a dose‐related increase in the incidence of dome‐shaped head was observed. Subsequent skeletal evaluation revealed delays in skull bone ossification and a widening of the frontal and frontoparietal sutures. Microphthalmia was also observed in two high‐dosage fetuses. A dose‐dependent and statistically significant reduction in maternal plasma retinol levels wa