Abstract
Paraquat (PQ) is a non-selective herbicide and is exceedingly toxic to humans. The mechanism of PQ toxicity is very complex and has not been clearly defined. There is no specific antidote for PQ poisoning. 5-hydroxy-1-methylhydantoin (HMH) is an intrinsic antioxidant and can protect against renal damage caused by PQ. The mechanism of PQ toxicology and the possible effects of HMH on PQ-induced lung injury were determined in this study. It was found that PQ decreased superoxide dismutase (SOD) activity and elevated the level of malondialdehyde (MDA), while HMH elevated SOD activity and decreased the level of MDA. Based on metabolomics, the citrate cycle, glutathione metabolism, taurine and hypotaurine metabolism, regulation of lipolysis in adipocytes, inflammatory mediator regulation of TRP channels, purine and pyrimidine metabolism, aldosterone synthesis and secretion, and phenylalanine metabolism were changed in the PQ group. Compared with the PQ group, the levels of N-acetyl-l-aspartic acid, L-glutamic acid, L-aspartic acid, mesaconic acid, adenosine 5′ monophosphate, methylmalonic acid, cytidine, phosphonoacetic acid, hypotaurine, glutathione (reduced) and cysteinylglycine increased, while the levels of corticosterone, xanthine, citric acid, prostaglandin G2, 4-pyridoxic acid and succinyl proline decreased in the HMH group. These metabolites revealed that HMH can alleviate inflammation caused by PQ and elevate the activity of intrinsic antioxidants. In conclusion, our results revealed PQ toxicology and the pharmacology underlying the protective effect of HMH on lung injury due to PQ. Toxicity caused by PQ results in lipid peroxidation and an increase in reactive oxygen species (ROS), nitric oxide (NO), damage to the biliary system, gastrointestinal system and nervous system, in addition to lungs, kidneys, and the liver. HMH is a good antioxidant and protects against lung injury caused by PQ. In summary, HMH efficiently reduced PQ-induced lung injury in mice.
Highlights
Paraquat (PQ, 1,1′-dimethyl-4-4′-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture
In this study, based on metabolomics and the detection of malondialdehyde (MDA) and superoxide dismutase (SOD), we assessed the protective mechanism of HMH against lung injury induced by PQ poisoning and supplement the PQ toxic mechanism
HMH was purchased from Shanghai Yanyi Biotechnology Co., Ltd. (Shanghai, China), PQ was from Shanghai Macklin Biotechnology Co., Ltd. (Shanghai, China), the BCA (Bicinchoninic acid) protein detection kit, and SOD total activity detection kit were from Beyotime Biological Reagent Co., Ltd. (Shanghai, China)
Summary
Paraquat (PQ, 1,1′-dimethyl-4-4′-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture. Following PQ poisoning, the lungs are the main target organs, and the redox reaction occurs after the uptake of PQ in the lungs, which interferes with mitochondrial electron transfer, generates a large number of oxygen free radicals, and induces lipid peroxidation injury[2]. Previous studies[13,14] have shown that HMH protects against PQ-induced kidney damage as it is oxidation resistant. In this study, based on metabolomics and the detection of malondialdehyde (MDA) and superoxide dismutase (SOD), we assessed the protective mechanism of HMH against lung injury induced by PQ poisoning and supplement the PQ toxic mechanism
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