Comparative teratogenicity and metabolism of all-trans retinoic acid, all-trans retinoyl β-glucose, and all-trans retinoyl β-glucuronide in pregnant Sprague-Dawley rats

When single large equimolar doses (0.38-0.41 mmol/kg BW) of all-trans retinoic acid (RA), all-trans retinoyl beta-glucose (RBGL), and all-trans retinoyl beta-glucuronide (RBG) are administered orally in oil on day 8.5 of pregnancy to Sprague-Dawley rats, RA and RBGL proved highly teratogenic, whereas RBG was not. Indeed, fetuses from RBG-treated dams were 16% heavier (P < 0.01) than control fetuses. After dosing with RA and RBGL, RA appeared in large amounts within 0.5 h in the maternal plasma and within 1.0 h in the embryo. In contrast, orally administered RBG seemed to be absorbed much more slowly, to be converted very slowly to RA, and not to accumulate either as RBG or as RA in the embryo. When incubated in vitro with embryos and attached membranes, however, both all-trans RBG and all-trans RA were partially converted to 13-cis RA. The nonteratogenicity of RBG, in contrast to RA, seems to be due to a much slower rate of GI absorption, a slow rate of hydrolysis to RA, a limited passage from the maternal circulation into the embryo, and a lower inherent toxicity.