Wnt/beta-catenin signaling pathway regulates the expression of drug metabolizing enzyme

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K23810
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0801:Pharmaceutical sciences and related fields
• Research Institution: Meijo University
• Principal Investigator: Sakakibara Yukiko 名城大学, 薬学部, 助教 (40848503)
• Project Period (FY): 2019-08-30 – 2022-03-31
• Keywords: 薬物代謝酵素 / Wnt/β-catenin経路 / UDP-グルクロン酸転移酵素 / 精神神経疾患

Outline of Final Research Achievements

The expression of the drug metabolizing enzymes is regulated by ligand-activated transcriptional factors. The purpose of the present study was to elucidate whether the expressions of UDP-glucuronosyltransferase isoforms are regulated by Wnt/β-catenin pathway, which is involved in embryonic development and tissue homeostasis.
Huh-7 cells were treated by 30 mM LiCl, that promotes transcriptional activation of target genes by β-catenin signaling pathway. Consequently, UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 mRNAs were increased by 2.5-, 6.4-, 2.8-, 3.3-, and 2.8-fold, respectively, following LiCl exposure for 72 hr in Huh-7 cells. Moreover, sulindac, which is known to suppress the expression of β-catenin, was exposed to Huh-7 cells with LiCl. As a result, the induction rates of UGT1A6 and UGT2B7 mRNAs were decreased by 1.8- and 1.2-fold, respectively. These results suggested that the expression of UGT1A6 and UGT2B7 mRNAs are regulated by Wnt/β- catenin pathway in Huh-7 cells.

Free Research Field

薬物代謝

Academic Significance and Societal Importance of the Research Achievements

個別化医療の実現のために、薬物の作用に影響する要因の解明は社会的意義が大きい。その要因の一つに、薬物代謝能の変動がある。本研究では、精神神経疾患の治療薬や、セロトニンやドーパミンなどの神経伝達物質の代謝に関与するUDP-glucuronosyltransferase (UGT) の発現変動の新たなメカニズムとして、Wnt/β-catenin経路の関与を明らかにした。この知見は、精神神経疾患における治療薬の開発ならびに薬物治療の戦略に重要な知見を付与すると考えられる。