| Hypolipidemic agent Z-guggulsterone: metabolisminterplays with induction of cholesteryl ester hydrolase ces1 and bile salt export pump. | |
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MedLine Citation:
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PMID: 22246918 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Z-Guggulsterone is a major ingredient in the Indian traditional hypolipidemic remedy guggul. A study in mice has established that its hypolipidemic effect involves the farnesoid X receptor (FXR), presumably by acting as an antagonist of this receptor. It is generally assumed that the antagonism leads to induction of cytochrome P450 7A1 (CYP7A1), the rate-limiting enzyme converting free cholesterol to bile acids. In this study, we tested whether Z-guggulsterone indeed induces human CYP7A1. In addition, the expression of cholesteryl ester hydrolase CES1 and bile salt export pump (BSEP) was monitored. In contrary to the general assumption, Z-guggulsterone did not induce CYP7A1. Instead, this phytosterol significantly induced CES1 and BSEP through transactivation. Z-Guggulsterone underwent metabolism by CYP3A4, and the metabolites greatly increased the induction potency on BSEP but not CES1. BSEP induction favors cholesterol elimination, whereas CES1 involves both elimination and retention (probably when excessively induced). Interestingly, clinical trials reported the hypolipidemic response rates from 18 to 80% and showed that higher dosages actually increased very low density lipoprotein cholesterol. Our findings predict that better hypolipidemic outcomes likely occur to individuals who have relatively higher capacity of metabolizing Z-guggulsterone with moderate CES1 induction, a scenario possibly achieved by lowering the dosing regimens. |
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Authors:
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Dongfang Yang; Jian Yang; Deshi Shi; Da Xiao; Yi-Tzai Chen; Chris Black; Ruitang Deng; Bingfang Yan |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-14 |
Journal Detail:
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Title: Journal of lipid research Volume: - ISSN: 0022-2275 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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University of Rhode Island, United States; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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