In cultured fetal rat bones, cyclohexanetriones that stimulate
prostaglandin synthesis inhibited
retinoic acid-induced cartilage degradation in a dose-dependent manner. The inhibition by the cyclohexanetrione
Ro 31-0521 was reversible, indicating that the effect was not due to cytotoxicity. Excess
retinoic acid is teratogenic in rats and adversely affects the normal differentiation of various morphogenetic systems, depending on the time of administration. The following
retinoic acid-induced malformations were suppressed by
Ro 31-0521: malformations of long bones and of apical phalanges induced on days 13 and 15 of gestation, respectively;
spina bifida and tail malformations induced on day 11 of gestation and
cleft palate induced on day 15 of gestation. However,
cleft palate and other head malformations including
exencephaly induced by
retinoic acid on day 11 of gestation were not suppressed but even increased by
Ro 31-0521. At a high dose,
Ro 31-0521 given alone on day 11 of gestation was embryolethal and teratogenic but was not on the tested other days, indicating that the cyclohexanetrione at specific stages and doses also interfered with normal morphogenesis like
retinoic acid. Assuming that stimulation of
prostaglandin synthesis is the main
biological effect of the cyclohexanetriones, our findings suggest that
prostaglandins may be involved in mediating
retinoid action.