THE INTERACTION OF HYDROPHOBIC BILE-ACIDS WITH THE ALPHA(1)-PROTEINASE INHIBITOR

An in vitro complex formation between cholesterol and human alpha(1)-proteinase inhibitor (alpha(1)-antitrypsin, alpha(1)-Pi) has been described. Hydrophobic bile acids were studied for a similar interaction using lithocholic acid (LC) as a prototype of a hydrophobic acid. At a molar ratio of 5:1, LC induced conformational changes of alpha(1)-Pi reflected in an abnormal gel-electrophoretic appearance, loss of anodal immunoreactivity on crossed immunoelectrophoresis, exposition of new antigenic determinant(s) on immunodiffusion, and loss of antiproteinase activity. After 6 h incubation, LC and alpha(1)-Pi form a complex of approximately 200 kDa molecular mass seen following gel-filtration. After prolonged (24 h) interaction a series of large alpha(1)-Pi polymers were seen on SDS-PAGE under reducing conditions followed by Western blotting. Glycolitho-, sulfolitho-, deoxycholic and 3-beta-hydroxy-5-cholenoic acids induced similar but less pronounced changes of alpha(1)-Pi, whereas transferrin remained unaffected. Hydrophilic acids lacked effect on alpha(1)-Pi. The results are compatible with a specific, irreversible interaction of alpha(1)-Pi with hydrophobic bile acids affecting its physical and proteinase inhibitory properties. The cholestatic potency of the hydrophobic acids studied and their ability to induce alpha(1)-Pi polymerization may be important in cholestatic conditions.