Andrographolide, an Antioxidant, Counteracts Paraquat- Induced Mutagenesis in Mammalian Cells.

Preechaya Tajai,Nuchanart Rangkadilok,John M Essigmann,Jutamaad Satayavivad,Tawit Suriyo,Bogdan Fedeles

doi:10.31557/apjcp.2021.22.s1.3

Abstract

Paraquat (1,1'-dimethyl, 4,4'-bipyridinium dichloride; PQ), a commonly used herbicide worldwide, is both toxic and mutagenic. The mutagenic effect of PQ stems from its ability to redox-cycle, generating oxidative stress and subsequently oxidative DNA damage, which miscodes when replication is attempted. Andrographolide (AP1), the major constituent in the leaves of the herbaceous plant Andrographis paniculata, is a diterpenoid with reported antioxidant activity. The present study employed the mammalian cell line AS52 to investigate the protective effect of AP1 against PQ-induced mutagenesis. AP1 induced cytotoxicity in AS52 cells in a dose-dependent manner (IC50 = 15.7 µM), which allowed the selection of a non-lethal dose for the mutagenesis studies. While PQ was mutagenic in AS52 cells as evidenced by the increased levels of 6-TGr mutants, AP1 by itself did not increase the mutation frequency. However, co-treatment with AP1 (1-5 µM) or the antioxidant N-acetylcysteine (2 mM) almost completely counteracted the mutagenicity of PQ (10-100 µM) in AS52 cells. Taken together, these findings suggest that AP1, and likely by extension, A. paniculata extracts, are effective antioxidants that can protect against PQ-induced mutations, and thus could be a promising alternative treatment for PQ poisoning.

Highlights

Paraquat (1,1’-dimethyl, 4,4’-bipyridinium dichloride; PQ) is one of the most widely used herbicides especially in developing countries including Thailand (Cocheme and Murphy, 2008; Blanco-Ayala et al, 2014; Tajai et al, 2018)
Co-treatment with AP1 (1-5 μM) or the antioxidant N-acetylcysteine (2 mM) almost completely counteracted the mutagenicity of PQ (10-100 μM) in AS52 cells. These findings suggest that AP1, and likely by extension, A. paniculata extracts, are effective antioxidants that can protect against PQ-induced mutations, and could be a promising alternative treatment for PQ poisoning
The key finding of the present study is that supplementation with antioxidants such as AP1 and NAC diminishes the oxidative stress levels and the level of mutagenesis induced by PQ (Figure 1)

Summary

Introduction

Paraquat (1,1’-dimethyl, 4,4’-bipyridinium dichloride; PQ) is one of the most widely used herbicides especially in developing countries including Thailand (Cocheme and Murphy, 2008; Blanco-Ayala et al, 2014; Tajai et al, 2018). An imbalance in the redox state of cells results in extensive mitochondrial damage and cell toxicity (Speit et al, 1998; Cocheme and Murphy, 2008; Blanco-Ayala et al, 2014). Our previous report showed that the mutagenicity of PQ increases significantly in our genetically engineered AS52 cell culture system that lacks the DNA repair proteins required to repair 8OG. This result suggests that genomic accumulation of 8OG is the main driver of PQ-induced mutagenesis (Tajai et al, 2018)

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