4.6

CiteScore

2.2

Impact Factor
  • ISSN 1674-8301
  • CN 32-1810/R
Muhammad Zubair Hafiz, Jie Pan, Zhiwei Gao, Ying Huo, Haobin Wang, Wei Liu, Jian Yang. Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) via dephosphorylation of EGFR signaling pathway[J]. The Journal of Biomedical Research. DOI: 10.7555/JBR.38.20240055
Citation: Muhammad Zubair Hafiz, Jie Pan, Zhiwei Gao, Ying Huo, Haobin Wang, Wei Liu, Jian Yang. Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) via dephosphorylation of EGFR signaling pathway[J]. The Journal of Biomedical Research. DOI: 10.7555/JBR.38.20240055

Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) via dephosphorylation of EGFR signaling pathway

  • This study aimed to assess the impact of timosaponin AⅢ (T-AⅢ) on drug-metabolizing enzymes in anticancer treatment. In vivo experiments were conducted on nude mice and ICR mice. After 24 days of T-AⅢ administration, nude mice showed an induction of CYP2B10, MDR1, and CYP3A11 in the liver. In ICR mice, CYP2B10 and MDR1 were up-regulated after three days of T-AⅢ administration. In vitro assessments were performed using HepG2 cells to determine the effects and underlying mechanisms. In HepG2 cells, T-AⅢ induced the expression of CYP2B6, MDR1, and CYP3A4, along with CAR activation. CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4. Furthermore, other CAR target genes showed a significant up-regulation. Up-regulation of mCAR was observed in the livers of nude mice and ICR mice. Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation, partially reversed by the MAPK/MEK activator t-BHQ. Inhibition of the ERK1/2 signaling pathway was also observed in vivo. Lastly, T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845, and suppressed EGF-induced phosphorylation of EGFR, ERK, and CAR. Additionally, T-AⅢ inhibited EGFR phosphorylation in nude mice. Our results demonstrate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.
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