Antioxidant Therapy Ameliorates Hepatotoxicity Induced by Microcystin-LR in an Oleic acid-induced Model of Hep3B Cells Mimicking the Diet-induced Mouse Model of Non-alcoholic Fatty Liver Disease

Apurva Lad, Jason Breuler, Prajwal Hegde, Fatimah Khalaf, Andrew L. Kleinhenz, Terry Hinds, Deepak Malhotra, Steven T. Haller, David J. Kennedy

Research output: Contribution to journalArticlepeer-review

Abstract

Microcystic-LR (MC-LR) is a potent hepatotoxin that has been evidenced to cause significant liver damage even at doses lower than the formerly specified No Observable Adverse Effect Level (NOAEL). We have previously observed that low dose exposure to MC-LR in animals with diet-induced Non-alcoholic Fatty Liver Disease (NAFLD) and their subsequent treatment with antioxidants like N-acetyl cystine (NAC) and the Na/K ATPase-Src kinase inhibitor pNaKtide significantly alleviated hepatic infiltration of immune cells, down regulated markers of inflammation and hepatotoxicity, increased the breakdown of the toxin molecule and re-stored phase I and phase II metabolism pathways of the drug including the glutathione pathway. Since the liver is composed of heterogeneous cell types, this study aimed to determine the specific role of hepatocytes in the uptake and metabolism of MC-LR, especially in the setting of NAFLD. To address this, we used two well-es-tablished hepatocyte cell lines-AML12 murine hepatocytes and human Hep3B hepatocytes. The cells were ex-posed to 10 µM of MC-LR in the presence and absence of pNaKtide (1 µM) and NAC (10 mM). We observed that exposure to MC-LR significantly increased markers of inflammation and hepatotoxicity, which were significantly attenuated with antioxidant treatment. To model steatosis hepatocytes characteristic of the NAFLD phenotype, cells were first treated with 500 µM of oleic acid (OA) before exposing them to the toxin in the presence and absence of antioxidants. MC-LR exposure induced markers of inflammation and hepatotoxicity that were significantly increased in the presence of OA as compared to MC-LR exposure alone. These were significantly attenuated with both pNaKtide (1 µM) and NAC (10 mM). These observations support the cen-tral role that hepatocytes play in the uptake and metabolism of MC-LR, which is convoluted by the presence of NAFLD-like conditions.

Original languageEnglish
Pages (from-to)377-379
Number of pages3
JournalLatin American Journal of Pharmacy
Volume42
Issue numberSpecial Issue
StatePublished - May 2023

Bibliographical note

Publisher Copyright:
© 2023, Colegio de Farmaceuticos de la Provincia de Buenos Aires. All rights reserved.

Keywords

  • Hep3B Cells
  • antioxidant therapy
  • microcystin-LR
  • oleic acid-induced model

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery

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