RETINYL METHYL-ETHER - BINDING TO TRANSPORT PROTEINS AND EFFECT ON TRANSCRIPTIONAL REGULATION

Retinyl methyl ether (RME), which prevents cancers of the rat mammary gland, binds to cellular retinol-binding protein and serum retinol-bin ding protein but not to cellular retinoic acid-binding protein or to t he nuclear retinoid receptors, RARs/RXRs. Since the biochemical effect s of retinoids likely involve activation or suppression of RAR/RXR-med iated gene transcription, we evaluated such activity of RME by perform ing cotransfection assays involving CV-1 cells, expression vectors con taining RAR and/or RXR cDNA, and an appropriate reporter vector. In th e concentration range of 10(-9)-10(-6)M, RME did not activate transcri ption by either of the heterodimers (RAR alpha, beta, or gamma/RXR alp ha) or the homodimer (RAR alpha/RAR alpha). The retinoid, however, exh ibited concentration-dependent inhibitory effects on the basal level o f transcriptional activity (no other retinoid added) of both the RAR b eta- and RAR gamma/RXR alpha heterodimers and of the retinoic acid-ind uced transcriptional activation of the RAR gamma/RXR alpha receptors. Thus, RME acted as a retinoic acid antagonist, a role possibly involve d in its cancer preventive activity. (C) 1996 Academic Press, Inc.