Where ferroptosis inhibitors and paraquat detoxification mechanisms intersect, exploring possible treatment strategies

Highlights

• Paraquat (PQ) toxicity is not solely but closely related to ferroptosis.

• Lipophilic antioxidants with anti-inflammatory properties mitigate PQ toxicity.

• NMDAR antagonists and iron-chelators prevent iron accumulation and PQ toxicity.

• ACSL4 and DPP-4 inhibitors as well as statins are promising in PQ toxicity.

• COX/LOX inhibitors and VDAC modulators demand further explorations.

Abstract

Paraquat (PQ) is a fast-acting and effective herbicide that is used throughout the world to eliminate weeds. Over the past years, PQ was considered one of the most popular poisoning substances for suicide, and PQ poisoning accounts for about one-third of suicides around the world. Poisoning with PQ may cause multiorgan failure, pulmonary fibrosis, and ultimately death. Exposure to PQ results in the accumulation of PQ in the lungs, causing severe damage and, eventually, fibrosis. Until now, no effective antidote has been found to treat poisoning with PQ. In general, the toxicity of PQ is due to the formation of high energy oxygen free radicals and the peroxidation of unsaturated lipids in the cell. Ferroptosis is the result of the loss of glutathione peroxidase 4 (GPX4) activity that transforms iron-dependent lipid hydroperoxides to lipid alcohols, which are inert in the biological environment. Impaired iron metabolism and lipid peroxidation are increasingly known as the driving agents of ferroptosis. The contribution of ferroptosis to the development of cell death during poisoning with PQ has not yet been addressed. There is growing evidence about the relationship between PQ poisoning and ferroptosis. This raises the possibility of using ferroptosis inhibitors for the treatment of PQ poisoning. In this hypothesis-driven review article, we elaborated how ferroptosis inhibitors might circumvent the toxicity induced by PQ and may be potentially useful for the treatment of PQ toxicity.

Introduction

Paraquat (PQ) is a non-selective, inexpensive, efficacious, and environmentally benign herbicide (Cui et al., 2018). These properties lead to its extensive application in many countries around the world. The first poisoning from this agent in humans was reported in 1966 (Bullivant, 1966), and also annually, it causes accidental and deliberate poisoning worldwide (Qing-Feng et al., 2012). It has been shown that PQ poisoning results in severe damage to kidneys, lungs, brain, and liver as well as other organs (Shadnia et al., 2018). Studies demonstrated that PQ poisoning is associated with complications such as acute lung failure, pulmonary hypertension, leukocytosis, metabolic acidosis, enlargement of heart, acute damage to the kidney, diffusion edema, and increased level of amylase, blood sugar, and creatinine (Delirrad et al., 2015). The following chart describes how medical attention toward paraquat is raised based on the number of PubMed articles each year (Fig. 1).

D'Souza et al. suggested that PQ is genotoxic and cytotoxic for male germ cells (D’Souza et al., 2006). Because of severe lung damage in acute exposure to the high dose of PQ and according to the recent reports which revealed its genotoxic nature and involvement in skin cancer and Parkinson’s disease (in long-term exposure to low dose of PQ), this herbicide received critical considerations in medicine and toxicology (Wesseling et al., 2001).

So far, no effective and safe antidote has been found for the treatment of PQ poisoning (Dinis-Oliveira et al., 2008). Regardless of the treatment, intoxication with PQ leads to death following several days in most patients due to multiorgan failure resulting from a decreased number of cells due to cell death. In various experimental models, cell death due to exposure to high doses of PQ by means of apoptosis has been suggested (Yamada et al., 2015). Surprisingly, in a study by Hirayama et al., it was shown that cell death in SH-SY5Y cell line caused by PQ should be complex and cannot be fully explained by known mechanisms (Hirayama et al., 2018).