2. Academic Validation
  3. Astragalus Polysaccharide Enhances Voriconazole Metabolism under Inflammatory Conditions through the Gut Microbiota

Astragalus Polysaccharide Enhances Voriconazole Metabolism under Inflammatory Conditions through the Gut Microbiota

  • J Clin Transl Hepatol. 2024 May 28;12(5):481-495. doi: 10.14218/JCTH.2024.00024.
Xiaokang Wang 1 2 3,  Xianjing Hu 2 4,  Chunxiao Ye 5,  Jingqian Zhao 6,  Shing Cheng Tan 7,  Liangbin Zhou 8,  Chenyu Zhao 6,  Kit Hang Wu 9,  Xixiao Yang 6,  Jinbin Wei 10,  Maoxun Yang 1 2 4
Affiliations

Affiliations

  • 1 The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong, China.
  • 2 Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, Guangdong Medical University, Dongguan, Guangdong, China.
  • 3 Department of Pharmacy, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong, China.
  • 4 Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China.
  • 5 Department of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 6 Department of Pharmacy, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, China.
  • 7 UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
  • 8 Department of Biomedical Engineering, Faculty of Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 9 Department of Pharmacy, Nossa Senhora do Carmo-Lago Health Centre, Health Bureau, Macau, China.
  • 10 Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China.
PMID: 38779521 DOI: 10.14218/JCTH.2024.00024
Abstract

Background and aims: Voriconazole (VRC), a widely used Antifungal drug, often causes hepatotoxicity, which presents a significant clinical challenge. Previous studies demonstrated that Astragalus polysaccharide (APS) can regulate VRC metabolism, thereby potentially mitigating its hepatotoxic effects. In this study, we aimed to explore the mechanism by which APS regulates VRC metabolism.

Methods: First, we assessed the association of abnormal VRC metabolism with hepatotoxicity using the Roussel Uclaf Causality Assessment Method scale. Second, we conducted a series of basic experiments to verify the promotive effect of APS on VRC metabolism. Various in vitro and in vivo assays, including cytokine profiling, immunohistochemistry, quantitative polymerase chain reaction, metabolite analysis, and drug concentration measurements, were performed using a lipopolysaccharide-induced rat inflammation model. Finally, experiments such as intestinal biodiversity analysis, intestinal clearance assessments, and Bifidobacterium bifidum replenishment were performed to examine the ability of B. bifidum to regulate the expression of the VRC-metabolizing enzyme CYP2C19 through the gut-liver axis.

Results: The results indicated that APS does not have a direct effect on hepatocytes. However, the assessment of gut microbiota function revealed that APS significantly increases the abundance of B. bifidum, which could lead to an anti-inflammatory response in the liver and indirectly enhance VRC metabolism. The dual-luciferase reporter gene assay revealed that APS can hinder the secretion of pro-inflammatory mediators and reduce the inhibitory effect on CYP2C19 transcription through the nuclear factor-κB signaling pathway.

Conclusions: The study offers valuable insights into the mechanism by which APS alleviates VRC-induced liver damage, highlighting its immunomodulatory influence on hepatic tissues and its indirect regulatory control of VRC-metabolizing Enzymes within hepatocytes.

Keywords

Anti-inflammatory responses; Astragalus polysaccharide; Bifidobacterium bifidum; Gut Microbiota; Hepatotoxicity; Metabolism; RUCAM; Voriconazole.

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