INHIBITION OF BILE-ACID CONJUGATION BY CYCLOSPORINE-A

Each of the two steps involved in bile acid conjugation was tested in vitro for its sensitivity to inhibition by cyclosporin A (CsA). Bile acid-CoA: glycine/taurine N-acyltransferase, the enzyme which catalyzes the second step, was tested and found to be insensitive to inhibition by 20 mu M CSA. Bile acid:CoA ligase, the enzyme which catalyzes the first step, was found to be inhibited by 25% at 10 mu M CsA in the standard assay. The inhibition was competitive vs. bile acid and noncompetitive vs. ATP, and uncompetitive vs. CoA. CsA was also found to interfere with the divalent cation requirement of the enzyme at low concentrations of Mg2+ the maximum inhibition was 70%. The maximum inhibition obtainable at physiologic Mg2+ concentration was 40%. The extent of inhibition was presumably limited by the insolubility of CsA. At concentrations of CsA reached in vivo during drug therapy, CsA can be expected to significantly inhibit bile acid conjugation.