Alteration of cAMP-mediated hormonal responsiveness by bile acids in cells of nonhepatic origin

Abstract

The present study was undertaken to determine whether bile acids could inhibit hormone-induced adenosine 3',5'-cyclic monophosphate (cAMP) production in cells of nonhepatic origin, as previously reported in the liver [Bouscarel et al., Am. J. Physiol. 268 (Gastrointest. Liver Physiol. 31): G300-G310, 1995]. The bile acids, ursodeoxycholic acid (UDCA), chenodeoxycholic acid, and deoxycholic acid inhibited prostaglandin E1 (PGE1)- and isoproterenol-induced cAMP production by 40-60% in human skin fibroblasts and human umbilical vein endothelial cells, respectively, to a similar extent as that observed in the liver. However, in both models, the taurine conjugates of these respective dihydroxy bile acids were without effect. After permeabilization of fibroblasts with saponin, UDCA, and its taurine conjugates inhibited hormone-induced cAMP production in a similar manner with a maximum inhibition of approximately 55%. The other taurine-conjugated dihydroxy bile acids were also able to inhibit PGE1-induced cAMP production. Furthermore, in human fibroblasts, UDCA was taken up in a dose- and time-dependent manner, whereas there was no uptake of taurocholic acid, even after 30 min of incubation. Therefore these results suggest that plasma membrane crossing of bile acids is a requirement for their inhibition of hormone-induced cAMP production. The ability of certain bile acids to affect hormone-induced cAMP production in extrahepatic tissues may be of pathophysiological significance in certain cholestatic liver diseases.