Inhibition of inflammation by SP600125 in cholestatic liver injury is dependent on the administration‑based exposure profile

  • Authors:
    • Xiuting Zheng
    • Manyun Dai
    • Gangming Xu
    • Liming Chang
    • Julin Yang
    • Aiming Liu
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  • Published online on: September 29, 2020     https://doi.org/10.3892/ijmm.2020.4742
  • Pages: 2271-2279
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Abstract

SP600125 is a classic inhibitor of c‑Jun‑N‑terminal kinase (JNK) that is widely used in numerous medicinal studies, but its administration regimen has yet to be optimized. In the present study, intraperitoneal (i.p.) and intragastric (i.g.) injections of 15 mg/kg SP600125 was performed in mice to compare the inhibitory effect against JNK signalling in cholestasis induced by α‑naphthylisothiocyanate (ANIT). SP600125 at a dose of 15 mg/kg administered by i.p. substantially decreased ANIT‑induced liver injury as observed by biochemical and histopathological examinations. The adaptation of bile acid synthesis was inhibited in the A‑SP‑i.p. group compared with that in the A‑SP‑i.g. group, as indicated by the expression analysis of CYP7A1 and CYP8B1. The transcription of the pro‑inflammatory factors IL‑6, IL‑1β, ICAM‑1 and IL‑10 supported the differential toxic responses. Western blot analysis revealed that JNK signalling activated by ANIT was inhibited more markedly in the A‑SP‑i.p. group than in the A‑SP‑i.g. group. The peak concentration and the AUC0‑24 of SP600125 in the A‑SP‑i.p. group were 5‑fold and 1.56‑fold higher, respectively, compared with those in the A‑SP‑i.g. group. These data indicated that i.p. administration of SP600125 produced a high plasma exposure profile, which directly determined its efficacy of blocking the JNK signalling. This effect of SP600125 on the JNK pathway may provide an optimized design for future in vivo investigations.
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December-2020
Volume 46 Issue 6

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Online ISSN:1791-244X

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Spandidos Publications style
Zheng X, Dai M, Xu G, Chang L, Yang J and Liu A: Inhibition of inflammation by SP600125 in cholestatic liver injury is dependent on the administration‑based exposure profile. Int J Mol Med 46: 2271-2279, 2020
APA
Zheng, X., Dai, M., Xu, G., Chang, L., Yang, J., & Liu, A. (2020). Inhibition of inflammation by SP600125 in cholestatic liver injury is dependent on the administration‑based exposure profile. International Journal of Molecular Medicine, 46, 2271-2279. https://doi.org/10.3892/ijmm.2020.4742
MLA
Zheng, X., Dai, M., Xu, G., Chang, L., Yang, J., Liu, A."Inhibition of inflammation by SP600125 in cholestatic liver injury is dependent on the administration‑based exposure profile". International Journal of Molecular Medicine 46.6 (2020): 2271-2279.
Chicago
Zheng, X., Dai, M., Xu, G., Chang, L., Yang, J., Liu, A."Inhibition of inflammation by SP600125 in cholestatic liver injury is dependent on the administration‑based exposure profile". International Journal of Molecular Medicine 46, no. 6 (2020): 2271-2279. https://doi.org/10.3892/ijmm.2020.4742