Biologically active compounds capable of stimulating gap junctional communication

Compounds with tumor-promoting or tumor-inhibiting activity such as phorbol esters, retinoic acid or beta-carotene, have been reported to modulate gap junctional communication (GJC). Chemicals exhibiting physiological or pathological properties were also tested in the dye-transfer assay to assess for their effects on GJC in human fibroblasts. Vitamin D induces GJC at concentrations between 10(-6) and 10(-8) M. The extent of induction is similar to that observed with retinoic acid. The physiologically active metabolite of vitamin D, 1,25-dihydroxy vitamin D, stimulates GJC at concentrations of 10(-8) to 10(-11) M. In fibroblasts devoid of a functional vitamin D receptor (VDR) there is no effect on GJC. Parallel to the increase in GJC there is a VDR-dependent increase in connexin43 protein and connexin43 mRNA levels. Apart from beta-carotene a variety of related carotenoids induce GJC at 10(-6) M, with six-membered ring compounds being more active than five-membered ring analogs. 4-Oxo-retinoic acid, a decompositon product of canthaxanthin in cell culture is active at even 10(-8) M. The data suggest that oxidation products of carotenoids are the ultimately active compounds responsible for the effects of carotenoids on GJC. The human teratogen thalidomide induces GJC in fibroblasts after activation by liver microsomes in concentrations as low as 10(-7) M. Treatment of cells with the thalidomide analog EM-12 stimulated GJC without prior activation. No effects on GJC were detected for phthalimide and glutamate, the components of thalidomide. However, 2-phthalimido glutaric acid (PGA), a hydrolysis product of thalidomide, raised GJC without activation at concentrations between 10(-10) M and 10(-3) M. It might be speculated that disturbances in GJC are in part related to the biological properties of thalidomide.