Elsevier, Journal of Lipid Research, 12(54), p. 3334-3344, 2013
DOI: 10.1194/jlr.m040519
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Increased levels of bile acids due to the various hepatic diseases could interfere with the metabolism of xenobiotics such as drugs, and endobiotics including steroid hormones. UDP-glucuronosyltransferases (UGTs) are involved in the conjugation and elimination of many xenobiotics and endogenous compounds. The present study sought to investigate the potential for inhibition of UGT enzymes by bile acids. The results showed that taurolithocholic acid (TLCA) exhibited the strongest inhibition towards UGTs, followed by lithocholic acid (LCA). Bile acids structure-UGT inhibition relationships were examined and in vitro-in vivo extrapolation performed by using in vitro inhibition kinetic parameters (Ki) in combination with calculated in vivo levels of taurolithocholic acid (TLCA). Substitution of a hydrogen with a hydroxyl group in the R1, R3, R4, R5 site of bile acids significantly weakens their inhibition ability towards most UGTs. The in vivo inhibition by taurolithocholate (TLCA) towards UGT forms was determined with following orders of potency: UGT1A4 > UGT2B7 > UGT1A3 > UGT1A1 ~ UGT1A7 ~ UGT1A10 ~ UGT2B15. In conclusion, these studies suggest that disrupted homeostasis of bile acids, notably taurolithocholic acid, found in various diseases such as cholestasis, could lead to altered metabolism of xenobiotics and endobiotics through inhibition of UGT enzymes.