EFFECT OF SELECTIVE ESTROGEN RECEPTOR MODULATORS ON LITHOCHOLIC ACID METABOLISM

Abstract

Lithocholic acid (LCA) is detoxified predominantly by sulfotransferase 2A1 and also metabolized by cytochrome P450 3A. In the present study, we investigated the effect of selective estrogen receptor modulators (SERMs) on LCA sulfation and LCA 3-oxidation. Among the SERMs investigated, bazedoxifene, arzoxifene, raloxifene, and lasofoxifene were the most potent inhibitors of human liver cytosol-catalyzed LCA sulfation. In the in vivo study, raloxifene and bazedoxifene decreased the levels of taurolithocholic acid sulfate and taurolithocholic acid in mouse liver. The findings from the structural metabolites/analogues of SERMs revealed the structural elements that play a role in the inhibition of LCA sulfation. In contrast to LCA sulfation, SERMs showed weak inhibition of human liver microsomal-catalyzed LCA 3-oxidation. Moreover, SERMs did not show time-dependent inhibition of LCA 3-oxidation. In conclusion, SERMs inhibited human liver cytosolic LCA sulfation, suggesting that SERMs may inhibit LCA sulfation in humans and may increase LCA-induced toxicity in the liver.