Livogrit prevents Amiodarone-induced toxicity in experimental model of human liver (HepG2) cells and Caenorhabditis elegans by regulating redox homeostasis

Abstract

Treatment with cationic amphiphilic drugs like Amiodarone leads to development of phospholipidosis, a type of lysosomal storage disorder characterized by excessive deposition of phospholipids. Such disorder in liver enhances accumulation of drugs and its metabolites, and dysregulates lipid profiles, which subsequently leads to hepatotoxicity. In the present study, we assessed pharmacological effects of herbal medicine, Livogrit, against hepatic phospholipidosis-induced toxicity. Human liver (HepG2) cells and in vivo model of Caenorhabditis elegans (N2 and CF1553 strains) were used to study effect of Livogrit on Amiodarone-induced phospholipidosis. In HepG2 cells, Livogrit treatment displayed enhanced uptake of acidic pH-based stains and reduced phospholipid accumulation, oxidative stress, AST, ALT, cholesterol levels, and gene expression of SCD-1 and LSS. Protein levels of LPLA2 were also normalized. Livogrit treatment restored Pgp functionality which led to decreased cellular accumulation of Amiodarone as observed by UHPLC analysis. In C. elegans, Livogrit prevented ROS generation, fat-6/7 gene overexpression, and lysosomal trapping of Amiodarone in N2 strain. SOD-3::GFP expression in CF1553 strain normalized by Livogrit treatment. Livogrit regulates phospholipidosis by regulation of redox homeostasis, phospholipid anabolism, and Pgp functionality hindered by lysosomal trapping of Amiodarone. Livogrit could be a potential therapeutic intervention for amelioration of drug-induced phospholipidosis and prevent hepatotoxicity.

GRAPHICAL ABSTRACT

Keywords:

• Hepatotoxicity
• Amiodarone
• Livogrit
• C. elegans
• Lysosomotropism
• Phospholipidosis

Acknowledgments

We thank Ms. Malini Rawat and Ms. Deepika Kumari for their support in biochemical analysis. We extend our gratitude to Ms. Meenu Tomer, Dr. Seema Gujral, and Dr. Jyotish Srivastava for their support in the UHPLC analysis. We are thankful to Mr. Devendra Kumawat for his help in preparation of graphical abstract. We are also grateful to Mr. Tarun Rajput and Mr. Gagan Kumar for their swift administrative support.

Disclosure statement

The test formulation (Livogrit) was sourced from Divya Pharmacy, Haridwar, Uttarakhand, India. Livogrit is a marketed medicinal product of Divya Pharmacy, Haridwar, India. AB is an honorary trustee in Divya Yog Mandir Trust, which governs Divya Pharmacy, Haridwar. In addition, he holds an honorary managerial position in Patanjali Ayurved Ltd, Haridwar, India. Divya Pharmacy, Haridwar and Patanjali Ayurved Ltd. Haridwar manufactures and sells many herbal medicinal products. Other than providing the test formulation (Livogrit), Divya Pharmacy was not involved in any aspect of the research reported in this study. All other authors have declared no competing interests.

Data availability statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Additional information

Funding

This research work was funded internally by Patanjali Research Foundation Trust, Haridwar, India.