Scoparone is a coumarin derivative and structurally belongs to the superfamily of polyphenolic compounds. This compound is abundant in Yin Chin (artemisiae scopariae), a Chinese herb that has been used for thousands of years to treat liver and kidney diseases. Yin Chin preparations have received much attention worldwide lately and are marketed as health supplements in North America. Scoparone is recognized as a major hepatic protective compound and has been shown to induce mouse uridine diphosphate-5?-glucuronosyltransferase-1A1 (UGT1A1), a bilirubin detoxification enzyme. We recently made an effort to test whether scoparone also induces human UGT1A1. Human primary hepatocytes were treated with scoparone or along with chenodeoxycholic acid (CDCA), an activator of the farnesoid X receptor (FXR). To our surprise, scoparone did not induce human UGT1A1, but instead significantly potentiated CDCA in inducing the bile salt export pump (BSEP). This biliary transporter is a target of CDCA-FXR signaling and plays an essential role in the secretion of bile acids. Consistent with the potentiation of BSEP induction, scoparone enhanced CDCA in activating FXR and the enhancement was much reduced with FXR phosphorylation-deficient mutants. In contrast, the enhancement was significantly increased in cells transfected with cytochrome P450 1A2 (CYP1A2), a drug-metabolizing enzyme. The central hypothesis of this project is that scoparone metabolites confer potent hepatic protection against cholestasis by efficaciously modulating FXR phosphorylation.
The specific aims are: (1) to determine the potentiation of BSEP induction as a function of scoparone metabolism;(2) to characterize the phosphorylation of FXR by scoparone;and (3) to define the role of the FXR and scoparone metabolism interplay in anti-cholestasis. To determine the metabolism of scoparone in general population, a large number of individual liver samples will be tested for the metabolism of scoparone. The major metabolites will be structurally determined and tested for the potentiation of BSEP induction. To test whether scoparone is a modulator of the phosphorylation of FXR, hepatocytes will be treated with scoparone alone or plus CDCA, and the phosphorylation status of FXR will be analyzed. To ascertain the anti-cholestatic potential of scoparone, mice will be subjected to inducing cholestasis with or without scoparone, and cholestatic markers and the metabolism of scoparone will be monitored. Overall, the proposed studies will establish the metabolic pathway of scoparone and the significance of the metabolism in bile acid elimination. Cholestasis is the most common form of hepatotoxicity, and the scoparone-rich herb Yin Chin has long been used to normalize liver functions. These studies will provide important information on how the hepatic protective activity is achieved. In addition, FXR is recognized as an important metabolic regulator and has anti-inflammatory effect. Interestingly, scoparone has been found to exert these very activities. Thus, a confirmation on the functional connection between FXR and scoparone will have broad mechanistic and therapeutic implications.

Public Health Relevance

The liver is the largest internal organ and has diverse functions including metabolism of drugs and elimination of metabolic wastes such as bile acids. As many as 10% Americans experience some liver abnormality, and elevated level of bile acids is the major form of liver dysfunctions. The Chinese herb Yin Chin (artemisiae scopariae) has been used to treat live illness for thousands of years. Yin Chin preparations have received much attention worldwide lately and are marketed as health supplements in North America. Scoparone is recognized as a major active compound with liver protective activity in Yin Chin. The proposed project will provide important new information on how scoparone normalizes liver functions and how Yin Chin preparations should be used to maximize the liver protective activity.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZAT1-PK (25))
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Pontzer, Carol H
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University of Rhode Island
Schools of Pharmacy
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