ALTERATION OF CAMP-MEDIATED HORMONAL RESPONSIVENESS BY BILE-ACIDS IN CELLS OF NONHEPATIC ORIGIN

The present study was undertaken to determine whether bile acids could inhibit hormone-induced adenosine 3',5'-cyclic monophosphate (cAMP) p roduction in cells of nonhepatic origin, as previously reported in the liver [Bouscarel et al., Am. J. Physiol. 268 (Gastrointest. Liver Phy siol. 31): G300-G310, 1995]. The bile acids, ursodeoxycholic acid (UDC A), chenodeoxycholic acid, and deoxycholic acid inhibited prostaglandi n E(1) (PGE(1))- and isoproterenol-induced cAMP production by 40-60% i n human skin fibroblasts and human umbilical vein endothelial cells, r espectively, to a similar extent as that observed in the liver. Howeve r, in both models, the taurine conjugates of these respective dihydrox y bile acids were without effect. After permeabilization of fibroblast s with saponin, UDCA, and its taurine conjugates inhibited hormone-ind uced cAMP production in a similar manner with a maximum inhibition of similar to 55%. The other taurine-conjugated dihydroxy bile acids were also able to inhibit PGE(1)-induced cAMP production. Furthermore, in human fibroblasts, UDCA was taken up in a dose- and time-dependent man ner, whereas there was no uptake of taurocholic acid, even after 30 mi n of incubation. Therefore these results suggest that plasma membrane crossing of bile acids is a requirement for their inhibition of hormon e-induced cAMP production. The ability of certain bile acids to affect hormone-induced cAMP production in extrahepatic tissues may be of pat hophysiological significance in certain cholestatic liver diseases.