Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor(CAR)via dephosphorylation of the EGFR signaling pathway
Muhammad Zubair Hafiz
Jie Pan
Zhiwei Gao
Ying Huo
Haobin Wang
Wei Liu
Jian Yang
Department of Pharmacology,Nanjing Medical University,Nanjing,Jiangsu 211166,China
摘要：The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver tissues.In the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢadministration.The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)activation.Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression.Furthermore,other CAR target genes also showed a significant increase in the expression.The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice.Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator t-BHQ.Inhibition of the ERK1/2 signaling pathway was also observed in vivo.Additionally,T-AⅢinhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and CAR.In the nude mice,T-AⅢ also inhibited EGFR phosphorylation.These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.
机标关键词：phosphorylationreceptorpathwayegfrdephactivatingandrostaneconstitutive
分类号：R966(药理学)
论文发表日期：2024-07-30
在线出版日期：2026-03-31（本平台首次上网日期，不代表文献的发表时间）
页数：16( 中插8,382-396 )
英文信息