A model of in vitro UDP-glucuronosyltransferase inhibition by bile acids predicts possible metabolic disorders

Zhong-Ze Fang,Rong-Rong He,Yun-Feng Cao,Naoki Tanaka,Changtao Jiang,Kristopher W Krausz,Yunpeng Qi,Pei-Pei Dong,Chun-Zhi Ai,Xiao-Yu Sun,Mo Hong,Guang-Bo Ge,Frank J Gonzalez,Xiao-Chi Ma,Hong-Zhi Sun

doi:10.1194/jlr.m040519

Abstract

Increased levels of bile acids (BAs) 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 BAs. The results showed that taurolithocholic acid (TLCA) exhibited the strongest inhibition toward UGTs, followed by lithocholic acid. Structure-UGT inhibition relationships of BAs 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 TLCA. Substitution of a hydrogen with a hydroxyl group in the R1, R3, R4, R5 sites of BAs significantly weakens their inhibition ability toward most UGTs. The in vivo inhibition by TLCA toward 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 BAs, notably taurolithocholic acid, found in various diseases such as cholestasis, could lead to altered metabolism of xenobiotics and endobiotics through inhibition of UGT enzymes.

Highlights

Increased levels of bile acids (BAs) due to the various hepatic diseases could interfere with the metabolism of xenobiotics, such as drugs, and endobiotics including steroid hormones
Among the tested BAs at 100 ␮l acetonitrile with 7-hydroxycoumarin (100 ␮M), TCDCA, taurocholic acid sodium salt hydrate, CDCA, ursodeoxycholic acid (UDCA), CA, dehydrocholic acid (DHCA), DCA, TUDCA, taurodeoxycholate hydrate (TDCA), and glycocholic acid hydrate (GCA) exhibited no or weak inhibition toward all the tested UGT forms, with inhibition magnitudes less than 90%
The role of BA in the activation of nuclear receptors might interfere with the evaluation of BA inhibition toward UGT enzymes

Summary

Introduction

Increased levels of bile acids (BAs) due to the various hepatic diseases could interfere with the metabolism of xenobiotics, such as drugs, and endobiotics including steroid hormones. Substitution of a hydrogen with a hydroxyl group in the R1, R3, R4, R5 sites of BAs significantly weakens their inhibition ability toward most UGTs. The in vivo inhibition by TLCA toward UGT forms was determined with following orders of potency: UGT1A4 > UGT2B7 > UGT1A3 > UGT1A1 ‫ف‬ UGT1A7 ‫ ف‬UGT1A10 ‫ ف‬UGT2B15. The in vivo inhibition by TLCA toward UGT forms was determined with following orders of potency: UGT1A4 > UGT2B7 > UGT1A3 > UGT1A1 ‫ف‬ UGT1A7 ‫ ف‬UGT1A10 ‫ ف‬UGT2B15 These studies suggest that disrupted homeostasis of BAs, notably taurolithocholic acid, found in various diseases such as cholestasis, could lead to altered metabolism of xenobiotics and endobiotics through inhibition of UGT enzymes.—Fang, Z-Z., R-R. UGT2B7 is the UGT isoform involved in the 3␣- and 6␣-glucuronidation of primary, secondary, and hydroxylated BA [9]

Methods

Results

Conclusion