Hypolipidemic agent Z-guggulsterone: metabolism interplays with induction of carboxylesterase and bile salt export pump

Hypolipidemic agent Z-guggulsterone: metabolism interplays with induction of carboxylesterase and bile salt export pump

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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 Mixer Attachements 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.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 on CES1.BSEP induction favors cholesterol elimination, whereas CES1 involves D-Mannose 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 VLDL cholesterol.Our findings predict that better hypolipidemic outcomes likely occur in individuals who have a relatively higher capacity of metabolizing Z-guggulsterone with moderate CES1 induction, a scenario possibly achieved by lowering the dosing regimens.