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A model of in vitro UDP-glucuronosyltransferase inhibition by bile acids predicts possible metabolic disorders
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
KeywordCholestasis Endobiotics Structure-udp-glucuronosyltransferase Inhibition Relationship Xenobiotics
Source PublicationJOURNAL OF LIPID RESEARCH
2013-12-01
DOI10.1194/jlr.M040519
Volume54Issue:12Pages:3334-3344
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectBiochemistry & Molecular Biology
WOS Research AreaBiochemistry & Molecular Biology
WOS KeywordFARNESOID-X-RECEPTOR ; HUMAN-LIVER ; HYODEOXYCHOLIC ACID ; NUCLEAR RECEPTOR ; GLUCURONIDATION ; ENZYME ; HEPATOCYTES ; CHOLESTASIS ; EXPRESSION ; INTESTINE
AbstractIncreased 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.
Language英语
WOS IDWOS:000330534900011
Citation statistics
Cited Times:56[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/137696
Collection中国科学院大连化学物理研究所
Affiliation1.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
GB/T 7714
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.
APA Fang, Zhong-Ze.,He, Rong-Rong.,Cao, Yun-Feng.,Tanaka, Naoki.,Jiang, Changtao.,...&Sun, Hong-Zhi.(2013).A model of in vitro UDP-glucuronosyltransferase inhibition by bile acids predicts possible metabolic disorders.JOURNAL OF LIPID RESEARCH,54(12),3334-3344.
MLA Fang, Zhong-Ze,et al."A model of in vitro UDP-glucuronosyltransferase inhibition by bile acids predicts possible metabolic disorders".JOURNAL OF LIPID RESEARCH 54.12(2013):3334-3344.
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