Toxicology of paraquat and pharmacology of the protective effect of 5-hydroxy-1-methylhydantoin on lung injury caused by paraquat based on metabolomics

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. Paraquat (PQ, 1,1′-dimethyl-4-4′-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture. The mortality rate of PQ poisoning is as high as 60-80%, mainly due to acute lung injury and progressive pulmonary fibrosis 1-3. Moreover, there is no specific antidote for PQ poisoning. 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. PQ enters the body and is excreted in the form of a prototype in the kidney, where the concentration is highest, resulting in impaired renal function. PQ cannot be excreted normally and further accumulates in the body; thus, involving other organs such as the liver, heart and lung, resulting in multiple organ failure 2. Creatinine is a degradation product of creatine, which is degraded at a constant rate. When renal function is impaired, large amounts of creatinine are acc...

Toward Regulatory Effects of Curcumin on Transforming Growth Factor-Beta Across Different Diseases: A Review

“…The reports display that 5–15 ml of 20% concentration of paraquat can result in moderate or severe poisoning ( Wesseling et al, 2001 ; Baltazar et al, 2013 ). Several studies have shown that exposing to paraquat can induce liver injury by decreasing antioxidant capacity and stimulation of inflammation ( Gao et al, 2020a ; Liu et al, 2020c ). Although studies have put much emphasis on the involvement of oxidative stress and inflammation in paraquat-mediated toxicity, the role of TGF-β signaling pathway is uncertain in liver toxicity.…”

Pesticide exposure and lung cancer risk: A case-control study in Nakhon Sawan, Thailand

“…Paraquat (dipyridylium), also known as Gramoxone, is a non-selective herbicide commonly used worldwide 33,37 . Although, the mechanism of toxicity has not been clearly defined, research found that paraquat can cause damage to the lungs, kidneys, and the liver 38 . At the cellular level, paraquat can produce reactive oxygen species (ROS), the superoxide free radical, which can initiate or promote carcinogenesis 39 .…”

Pesticide exposure and lung cancer risk: A case-control study in Nakhon Sawan, Thailand

“…Although, the mechanism of toxicity has not been clearly defined, research found that paraquat can cause damage to the lungs, kidneys, and the liver 38 . At the cellular level, paraquat can produce reactive oxygen species (ROS), the superoxide free radical, which can initiate or promote carcinogenesis 39 .…”