Paraquat's primary mechanism of toxicity is its ability to undergo redox cycling within cells, particularly in mitochondria. It accepts an electron from a donor molecule (such as NADPH) to form a paraquat radical, which then rapidly reacts with molecular oxygen to generate the superoxide anion (O2•−), a reactive oxygen species (ROS). This process regenerates the paraquat dication, allowing it to undergo multiple rounds of redox cycling and producing large amounts of superoxide. The superoxide radical can then dismutate to hydrogen peroxide (H2O2) and, in the presence of iron, can form the highly reactive hydroxyl radical (•OH). These ROS cause extensive oxidative damage to cellular lipids, proteins, and DNA, leading to cell death. In the lungs, paraquat is selectively taken up by alveolar epithelial cells via a polyamine transport system, leading to its accumulation and causing severe lung damage, a hallmark of paraquat poisoning. The compound also affects other organs, including the kidneys, liver, and heart, leading to multiple-system organ damage. Its ability to induce oxidative stress and its selective accumulation in the lungs make it a potent and dangerous toxin.

The LD50 of paraquat in different animals [2] is determined by the number of animals in each group, their body weight (g), and the route of administration (mg/kg). Female rats 6 130-160 Oral 112 (104-122) Female rats 10 150-205 Oral 150 (139-162) Female rats 6 130-160 Intraperitoneal 19 (16-21) Female rat 6 130-160 Intraperitoneal 16 (14-19) Female guinea pig 3 400 -500 intraperitoneal injection 3 Male guinea pig 5 190-250 oral 262 (200-346) Female cat 3 2500-4400 oral 35 (27 –46)

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In vitro studies have extensively characterized paraquat's mechanism of toxicity. The primary activity measured is its ability to induce oxidative stress in cell cultures. In a typical experiment, cells (e.g., neuronal cells, lung epithelial cells, or fibroblasts) are treated with paraquat at various concentrations (typically in the micromolar to millimolar range). The production of ROS is measured using fluorescent probes such as 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA), which becomes fluorescent upon oxidation. An increase in fluorescence indicates an increase in ROS production. Lipid peroxidation is measured by the formation of malondialdehyde (MDA) using the thiobarbituric acid reactive substances (TBARS) assay. The activity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), is measured to assess the cellular response to oxidative stress. Cell viability is measured using assays like MTT or LDH release. These in vitro studies have confirmed that paraquat is a potent inducer of oxidative stress and cell death. They are also used to study the protective effects of antioxidants against paraquat toxicity.

In vivo studies have demonstrated the extreme toxicity of paraquat in animal models. In acute toxicity studies, paraquat is administered to rodents (typically rats) by oral gavage. The animals are observed for signs of toxicity, and the LD50 (lethal dose for 50% of the population) is determined. The LD50 of paraquat in rats is approximately 100 mg/kg, but it can vary. In subacute and chronic toxicity studies, animals are given lower doses of paraquat daily for a period of weeks or months. Organ toxicity is assessed by histopathological examination of tissues, particularly the lungs, kidneys, and liver. Paraquat is known to cause severe lung damage, characterized by pulmonary fibrosis and edema. It also causes damage to the kidneys and liver. In addition to its acute toxicity, paraquat has been studied in models of Parkinson's disease. Administration of paraquat to mice has been shown to cause the loss of dopaminergic neurons in the substantia nigra, a hallmark of Parkinson's disease. These in vivo studies are crucial for understanding the toxicological profile of paraquat and for assessing its risk to human health and the environment.

There are no specific in vitro receptor or enzyme binding assays for paraquat, as it does not act by binding to a specific receptor or enzyme. Its mechanism of action is based on redox cycling, not on inhibiting a particular protein. However, its effects can be studied by measuring its impact on the activity of enzymes involved in oxidative stress. For example, the activity of superoxide dismutase (SOD) can be measured in cells or tissues treated with paraquat. SOD is an antioxidant enzyme that converts superoxide to hydrogen peroxide. An increase in SOD activity may indicate a cellular response to increased superoxide production. The activity of catalase, which breaks down hydrogen peroxide, can also be measured. Additionally, the levels of glutathione, a major cellular antioxidant, can be measured, as it is often depleted by oxidative stress. These are not direct binding assays but rather assays that measure the downstream consequences of paraquat's redox activity. They are used to characterize the cellular response to oxidative stress.

In vitro cell-based assays for paraquat are used to study its cytotoxic effects and the mechanisms of oxidative stress. A typical assay involves culturing a relevant cell line (e.g., rat pheochromocytoma PC12 cells for neuronal studies, or human lung epithelial A549 cells for pulmonary studies) in multi-well plates. The cells are treated with paraquat at various concentrations (e.g., 0.1-10 mM) for a defined period (e.g., 24-48 hours). Cell viability is then assessed using a colorimetric assay such as MTT, which measures the metabolic activity of living cells. A decrease in MTT reduction indicates a loss of cell viability. To specifically measure oxidative stress, cells can be loaded with the fluorescent probe H2DCFDA. After treatment with paraquat, the fluorescence intensity is measured using a microplate reader or flow cytometry. An increase in fluorescence indicates increased ROS production. The levels of lipid peroxidation can be measured by the TBARS assay. The activity of antioxidant enzymes (SOD, CAT, GPx) can be measured in cell lysates. These assays provide a comprehensive picture of paraquat's cytotoxicity and the underlying oxidative stress mechanisms. They are also used to screen for potential protective agents.

In vivo animal experiments for paraquat are primarily conducted to study its toxicological effects and to test potential antidotes. A standard acute toxicity study involves administering a single dose of paraquat to rats or mice, typically by oral gavage. The animals are observed for 14 days, and mortality is recorded. The LD50 is calculated. For studying the mechanism of toxicity, animals are given a sublethal dose of paraquat, and tissues (particularly the lungs, liver, and kidneys) are harvested at various time points. These tissues are analyzed for markers of oxidative stress (e.g., MDA, glutathione levels) and for histopathological changes. Studies have shown that superoxide dismutase (SOD) protects against the development of acute paraquat toxicity in rats. This has been demonstrated by administering SOD (or a SOD mimetic) along with paraquat and observing a reduction in toxicity. These animal models are critical for understanding the pathophysiology of paraquat poisoning and for developing therapeutic strategies, although there is currently no effective antidote for paraquat poisoning.

Metabolism / Metabolites
Oral absorption of paraquat is low. It is not metabolized but reduced to unstable free radicals, which are then re-oxidized to form cations and produce superoxide anions. It is primarily excreted in urine, with small amounts also excreted in feces (A606, L1008). Biological Half-Life Animal studies: less than 6 hours; other animal studies have found paraquat detectable up to 26 days after ingestion; [TDR, page 991]

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Paraquat is rapidly absorbed after ingestion and is distributed throughout the body. It is not metabolized to a significant extent and is primarily excreted unchanged in the urine. Its half-life in the body is relatively short (hours), but it accumulates in the lungs, where it has a much longer half-life (days to weeks). This selective accumulation in the lungs is responsible for its characteristic pulmonary toxicity. Paraquat has a molecular weight of 257.16 g/mol and is a small, hydrophilic molecule. It is a dicaiton at physiological pH, which limits its ability to cross lipid membranes. Its uptake into cells, particularly lung epithelial cells, is mediated by a polyamine transport system. This active transport is responsible for its selective accumulation in the lungs. For research use, paraquat dichloride is typically supplied as a solid and is soluble in water. Its stability is ensured by storing it under recommended conditions. Understanding its PK is crucial for understanding its toxicity and for designing therapeutic interventions.

Toxicity Summary
The toxic mechanism of paraquat primarily stems from metabolically catalyzed single-electron redox reactions, leading to intracellular NADPH depletion and the generation of potentially toxic oxygen free radicals (such as superoxide anion radicals (A6O7)). Recent studies have shown that paraquat cytotoxicity mainly occurs in mitochondria, particularly in mitochondria-rich tissues. NADH-dependent paraquat reductase, containing voltage-dependent anion channel 1 (VDAC1) in mitochondria, appears to be the primary cause of paraquat cytotoxicity. When mitochondria are incubated with NADH and paraquat, superoxide anions are generated, leading to mitochondrial rupture. Mitochondrial rupture results in rapid cell death (A3102). Toxicity Data
LCLo (rat) of inhalable dust = 1 mg/m3/6H; LD50: 150 mg/kg (oral, rat) (L1008); LD50: >480 mg/kg (skin, rabbit) (L1008)

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Paraquat is extremely toxic to humans and animals. It causes severe, often fatal, poisoning. The primary target organs are the lungs, where it causes pulmonary fibrosis and damage to the alveolar epithelium, leading to respiratory failure. It also causes damage to the kidneys (acute kidney injury) and liver. Ingestion of even a small amount (e.g., 10-15 mL of a 20% solution) can be fatal. There is no specific antidote for paraquat poisoning. Treatment is supportive and focuses on reducing absorption (e.g., by activated charcoal) and enhancing elimination (e.g., by hemodialysis). Concentrated solutions (>20%) can cause severe corrosive injury upon ingestion, injection, or skin/eye contact. Long-term exposure to paraquat has been linked to the development of Parkinson's disease. Due to its extreme toxicity, its use is highly restricted or banned in many countries. It is classified as a hazardous substance and must be handled with extreme caution, using appropriate personal protective equipment (PPE).

[1]. Hamadi NK, et al. Adsorption of Paraquat dichloride from aqueous solution by activated carbon derived from used tires. J Hazard Mater. 2004 Aug 9;112(1-2):133-41.
[2]. Clark D G, et al. The toxicity of paraquat[J]. Occupational and Environmental Medicine, 1966, 23(2): 126-132.
[3]. Ladipo M K, et al. Acute Toxicity, Behavioural Changes and Histopathological Effect of Paraquat Dichloride on Tissues of Catfish (Clarias Gariepinus)[J]. International Journal of Biology, 2011.
[4]. Lock E A, et al. Paraquat[M]//Hayes' Handbook of Pesticide Toxicology. Academic Press, 2010: 1771-1827.

Paraquat dichloride is a colorless to yellow crystalline solid used as a contact herbicide and desiccant. (EPA, 1998) Paraquat dichloride is an organochloride salt with herbicidal and photosystem I inhibitor properties; its main component is paraquat. Paraquat dichloride is one of the ingredients in many commercial herbicides. The vast majority (93%) of paraquat poisoning deaths are intentional suicides. In developing countries, paraquat is a leading suicide drug. For example, between 1979 and 2001, 70% of suicides in Samoa were due to paraquat poisoning; between 1996 and 1997, 76% of suicides in southern Trinidad were due to paraquat poisoning. However, some independent institutions have also studied this use of paraquat. Jenny Pronczuk de Garbino noted that there have never been any cases of cannabis users suffering lung or other damage due to paraquat contamination. A manual from the U.S. Environmental Protection Agency also states: "...the toxicity caused by this mechanism is very rare or non-existent." Most paraquat contaminating cannabis decomposes into dipyridine during ingestion, a product of the combustion of cannabis leaves themselves, and has very low toxicity. Paraquat is the trade name for N,N-dimethyl-4,4'-bipyridine dichloride, one of the most widely used herbicides in the world. Paraquat is a violaride herbicide, fast-acting and non-selective, killing green plant tissue upon contact. Ingestion of paraquat is also toxic to humans. Paraquat is a quaternary ammonium salt herbicide, also one of the most widely used herbicides in the world. It acts rapidly and non-selectively, killing green plant tissue upon contact. It redistributes within the plant but does not damage mature bark. As a herbicide, paraquat protects crops by controlling a variety of annual and some perennial weeds that compete with crops for water, nutrients, and sunlight, thus reducing crop yield and quality. Ingestion of pure paraquat is highly toxic to mammals and humans, potentially causing acute respiratory distress syndrome (ARDS), for which there is currently no specific antidote. However, bleaching soil or activated charcoal are effective treatments if ingested promptly. Death can occur within 30 days of ingestion. Diluted paraquat used for spraying is less toxic; therefore, the greatest risk of accidental poisoning occurs during the mixing and loading of paraquat. Paraquat is a toxic dipyridine compound used as a contact herbicide. Contact with concentrated solutions can cause skin irritation, nail splitting and shedding, and delayed wound healing. See also: Paraquat (note moved to).

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Paraquat dichloride is a commercial herbicide, not a therapeutic drug. It is one of the most widely used herbicides in the world, despite its extreme toxicity. Its mechanism of action as an herbicide is the same as its mechanism of toxicity: it induces the production of superoxide radicals in plant cells, causing oxidative damage and cell death. It is a non-selective contact herbicide, meaning it kills any green plant tissue it comes into contact with. Its use is highly regulated due to its toxicity to humans and the environment. In many countries, its use has been banned or severely restricted. Paraquat is also used as a research tool to study oxidative stress and the mechanisms of cell death, and it is particularly used in models of Parkinson's disease. It is also used to study the mechanisms of acute lung injury and fibrosis. As a research compound, it is a valuable tool for understanding the role of oxidative stress in disease, but it is extremely dangerous and must be handled with the utmost care.

C12H14CL2N2

257.16

256.053

1910-42-5

1910-42-5 (chloride);1983-60-4 (iodide);4685-14-7 (cation);75365-73-0 (Chloride hydrate);

15938

Typically exists as solid at room temperature

1.25

175ºC

>300 °C(lit.)

0

2

1

16

145

0

C[N+]1=CC=C(C=C1)C2=CC=[N+](C)C=C2.[Cl-].[Cl-]

FIKAKWIAUPDISJ-UHFFFAOYSA-L

InChI=1S/C12H14N2.2ClH/c1-13-7-3-11(4-8-13)12-5-9-14(2)10-6-12;;/h3-10H,1-2H3;2*1H/q+2;;/p-2

1-methyl-4-(1-methylpyridin-1-ium-4-yl)pyridin-1-ium;dichloride

Paraquat dichloride NSC-263500 NSC 263500

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)