tretinoin and 3-4-didehydroretinyl-acetate

All-trans-3,4-Didehydroretinoic acid (vitamin A2 acid; DDRA) is one of the retinoids present in human skin, the most responsive tissue to retinoid treatment. To understand the mechanism of action of DDRA in the control of differentiation and tumorigenesis, we studied its interaction with cellular retinoic acid-binding proteins (CRABPs) and nuclear all-trans-retinoic acid (RA) receptors (RARs), and 9-cis-retinoic acid receptors (RXRs). The IC50 plots of DDRA for inhibition of [3H]RA binding to CRABP I and II and to RAR alpha, beta and gamma illustrate that this retinoid binds with the same affinity as RA to these proteins. DDRA, however, showed higher affinity than RA for RXR alpha. Evaluation of the transcriptional activation potential of DDRA in CV-1 cells showed that this retinoid induced RAR alpha-mediated transcription to the same magnitude as RA in the 10(-9) to 10(-6) M concentration range. However, in comparison to RA, DDRA produced a 2- to 3-fold higher activation of the transcription mediated by RXR alpha homodimers, as well as RAR beta-RXR alpha heterodimers. These results suggest that the biological activity of retinoids in the skin may be attained through the joint potential of both RA and DDRA.

Topics: Animals; Binding, Competitive; COS Cells; Humans; Mice; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Transcription, Genetic; Transfection; Tretinoin; Vitamin A

The teratogenic potencies of the all-trans isomers of retinoic acid (RA), 3,4-didehydroretinyl acetate (A2), and retinyl acetate (A1) were compared. Groups of eight timed-pregnant Sprague-Dawley rats were administered single equimolar doses (3.5-352 mumol/kg BW) of the retinoids orally in oil on day 8.5 of pregnancy, and dams and fetuses were sacrificed on day 19. The relative teratogenicity and embryolethality of the three tested retinoids were: RA > A2 > A1. The no-effect level of RA and A2 was 3.5 mumol/kg BW and of A1 was 35 mumol/kg BW. Whereas the adverse effects of RA and A1 were dose dependent, A2 showed biphasic effects, with a peak of embryolethality at 35 mumol/kg BW. Dams also exhibited weight loss and other toxic manifestations from doses of A2 and Ra > or = 35 mumol/kg BW. In dosed dams, (1) Liver concentrations of A1 and A2 increased with the doses of A1 and A2, respectively, (2) RA had little effect on liver A1 except for an increase at the highest toxic dose, and (3) A2 showed a sparing effect on liver A1. RA, although not detected in fetuses from dams treated with A1, was present in significant concentrations (0.5-4.1 nmol/g liver) in fetuses from dams treated with A2. The biphasic change in embryolethality with the dose of A2 correlates with this enhanced concentration of fetal RA. We hypothesize that the actual teratogen in the fetuses of A2-dosed dams is RA. A2 might induce this biphasic effect by inhibiting the catabolism of RA at lower doses and its formation at higher doses.

Topics: Animals; Diterpenes; Female; Fetal Resorption; Isomerism; Liver; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley; Retinyl Esters; Teratogens; Tretinoin; Vitamin A