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题名: A model of in vitro UDP-glucuronosyltransferase inhibition by bile acids predicts possible metabolic disorders
作者: Fang, Zhong-Ze1, 2, 4;  He, Rong-Rong5;  Cao, Yun-Feng2;  Tanaka, Naoki4;  Jiang, Changtao4;  Krausz, Kristopher W.4;  Qi, Yunpeng4;  Dong, Pei-Pei6;  Ai, Chun-Zhi2;  Sun, Xiao-Yu2;  Hong, Mo2;  Ge, Guang-Bo2;  Gonzalez, Frank J.4;  Ma, Xiao-Chi7;  Sun, Hong-Zhi1
关键词: cholestasis ;  endobiotics ;  structure-UDP-glucuronosyltransferase inhibition relationship ;  xenobiotics
刊名: JOURNAL OF LIPID RESEARCH
发表日期: 2013-12-01
DOI: 10.1194/jlr.M040519
卷: 54, 期:12, 页:3334-3344
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Biochemistry & Molecular Biology
研究领域[WOS]: Biochemistry & Molecular Biology
英文摘要: 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 (K-i) 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 similar to UGT1A7 similar to UGT1A10 similar to 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.
关键词[WOS]: FARNESOID-X-RECEPTOR ;  HUMAN-LIVER ;  HYODEOXYCHOLIC ACID ;  NUCLEAR RECEPTOR ;  GLUCURONIDATION ;  ENZYME ;  HEPATOCYTES ;  CHOLESTASIS ;  EXPRESSION ;  INTESTINE
语种: 英语
WOS记录号: WOS:000330534900011
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/137696
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China
3.Liaoning Med Univ, Affiliated Hosp 1, Dalian 116023, Peoples R China
4.NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA
5.Jinan Univ, Coll Pharm, Guangzhou 510632, Guangdong, Peoples R China
6.Dalian Med Univ, Acad Integrat Med, Dalian 116044, Peoples R China
7.Dalian Med Univ, Coll Pharm, Pharmacokinet & Drug Transport Key Lab, Dalian 116044, Peoples R China

Recommended Citation:
Fang, Zhong-Ze,He, Rong-Rong,Cao, Yun-Feng,et al. A model of in vitro UDP-glucuronosyltransferase inhibition by bile acids predicts possible metabolic disorders[J]. JOURNAL OF LIPID RESEARCH,2013,54(12):3334-3344.
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