Target: HPPD enzyme[1]
4-Hydroxyphenylpyruvate dioxygenase (HPPD) in plants. Mesotrione is a potent and competitive reversible inhibitor of the HPPD enzyme (K1 ~6-18 pM). In addition to its primary herbicidal mechanism, mesotrione also exhibits small molecule agonist activities for retinoid X receptor alpha, estrogen receptor alpha, androgen receptor signaling, and activates antioxidant response element (ARE) signaling and human pregnane X receptor (PXR) signaling in mammalian systems.

Mesotrione has an estimated Ki value of 6±18pM at 25°C, making it a strong inhibitor of the HPPD enzyme. Arabidopsis thaliana (L) is the source of HPPD[1].

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Mesotrione is a potent HPPD enzyme inhibitor, with an estimated K1 value in the range of 6-18 pM at 25degC using HPPD from Arabidopsis thaliana. In cell-free enzyme assays, it shows competitive and reversible inhibition of HPPD. The compound also demonstrates inhibitory action on tyrosine aminotransferase (TAT) in human fibroblasts and HPPD in human and rat models with low Ki/IC₅0 values. It exhibits diverse bioactivities including activation of several nuclear receptor signaling pathways (RXRalpha, ERalpha, AR) and inhibition of glutaminase (GLS) and tyrosyl-DNA phosphodiesterase 1 (TDP1).

In rats and mice, mesotrione (oral administration; 1 mg/kg; single dosage) is rapidly and widely absorbed. urine excretione is evaluated after a single dosage; in males, the estimated absorption values for urine excretione ranged from 62.2% to 68.3%. For every gender, the mean peak blood concentration (Cmax) of radioactivity was recorded 0.5 hours post-dosing[1].

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In vivo herbicidal activity: Mesotrione demonstrates significant herbicidal effects in various weed species including Amaranthus tuberculatus, Digitaria sanguinalis, Amaranthus retroflexus, Brassica rapa subsp. oleifera, and Echinochloa crus-galli, inhibiting both fresh weight and root growth with high efficacy. In rats and mice, oral administration (1 mg/kg, single dose) is rapidly and extensively absorbed. Mean peak blood concentration (Cmax) of radioactivity occurs 0.5 hours after dosing. Urinary excretion values range from 62.2% (males) to 68.3% (females). The compound also shows significant reduction in blood tyrosine levels in in vivo studies.

In vitro HPPD enzyme inhibition assay: HPPD enzyme (typically from Arabidopsis thaliana) is incubated with various concentrations of Mesotrione (0.001-100 microM) in assay buffer containing 4-hydroxyphenylpyruvate (4-HPP) as substrate. The reaction is carried out at 25degC for 5-10 minutes. The product, homogentisate, is quantified by HPLC or by measuring absorbance at 310 nm. Alternatively, a coupled assay with homogentisate dioxygenase can be used. The inhibition constant (Ki) is determined using Lineweaver-Burk plot analysis. IC₅0 values for HPPD inhibition are calculated from concentration-response curves. Mesotrione is used as a positive control in many HPPD inhibitor discovery studies.

For cell-based studies, plant cells or seedlings can be used. For weed control efficacy, seeds of target weed species (e.g., Amaranthus retroflexus, Digitaria sanguinalis) are germinated in pots. Mesotrione is applied post-emergence at various concentrations (0-500 g a.i./ha) or pre-emergence. Fresh weight and root growth inhibition are measured after 7-14 days. Phytotoxicity is assessed visually. For mammalian cell studies, human cell lines (e.g., hepatocytes, fibroblasts) are treated with Mesotrione (0.1-100 microM) for 24-72 hours. Cell viability is assessed by MTT assay. Gene expression (e.g., CYP enzymes, nuclear receptors) is analyzed by qPCR. HPPD activity in cell lysates can be measured using the enzyme assay described above.

Animal herbicidal efficacy studies: Weed species are grown in pots or field plots. Mesotrione is applied pre-emergence or post-emergence at recommended rates (typically 70-225 g a.i./ha). Weed control efficacy is assessed visually as percentage control or by measuring weed biomass at 2-4 weeks after treatment. Crop safety is evaluated by assessing phytotoxicity symptoms (e.g., bleaching, stunting) and yield parameters. For absorption, distribution, metabolism, and excretion (ADME) studies in rats/mice: Single oral dose of 14C-labeled Mesotrione (1 mg/kg). Blood, urine, feces, and tissues are collected at various time points. Radioactivity is measured by liquid scintillation counting or quantitative whole-body autoradiography (QWBA). Metabolites are identified by LC-MS/MS.

Absorption, Distribution and Excretion
Approximately 70% of mesotrione is absorbed within 72 hours. Mesotrione is widely distributed, with the highest residual levels in the liver and kidneys at 72 hours. No accumulation was observed. 65-70% is excreted within 72 hours, primarily via urine (55%). NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulfonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are both 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors. NTBC has been successfully used to treat hereditary tyrosinemia type 1 (HT-1), while mesotrione has been developed as a herbicide. This study investigated the pharmacokinetics of these two compounds following a single oral administration in healthy male volunteers. The NTBC study aimed to evaluate the bioequivalence of the two different formulations and determine the extent to which they induce tyrosinemia. The mesotrione study aimed to determine the extent and duration of its effect on tyrosine catabolism. Additionally, the excretion of unmesotrione in urine was measured to assess the importance of this clearance pathway and to aid in the development of occupational exposure surveillance strategies. …A total of 28 volunteers participated in two independent compound studies. In the first study, the relative bioavailability of NTBC in liquid and capsule formulations was compared, and its effect on plasma tyrosine concentrations was measured. In the second study, the pharmacokinetics of mesotrione at three doses were determined. Plasma tyrosine concentrations were monitored, and the excretion of mesotrione and its tyrosine metabolites in urine was measured. Both compounds were well tolerated at the studied dose levels. Following a single oral dose of 1 mg/kg body weight of NTBC (both formulations), peak plasma concentrations of NTBC were rapidly reached, with a plasma half-life of approximately 54 hours. The mean (± standard deviation) AUC(0,∞) (capsules 602±154 μg/ml·h vs solution 602±146 μg/ml·h) and t1/2 (capsules 55±13 hours vs solution 54±8 hours) of the two formulations showed no statistically significant differences, supporting the bioequivalence of the two formulations. Mesylate is also rapidly absorbed, with a significant portion of the dose excreted unchanged in the urine. Its plasma half-life is approximately 1 hour, independent of dose, and AUC(0,∞) and Cmax increase linearly with dose. After administration of 1 mg/kg (both formulations) of NTBC, plasma tyrosine concentrations increased to approximately 1100 nmol/ml. At 14 days post-administration, tyrosine concentrations remained approximately 8 times the background level, but returned to background levels within 2 months after the second dose. After administration of mesylate, tyrosine concentrations increased, reaching a peak of approximately 300 nmol/ml at a dose of 4 mg/kg body weight. Within 2 days after administration, tyrosine concentrations returned to background levels. Within 24 hours of administration of 4 mg/kg mesotrione, urinary excretion of tyrosine metabolites increased, but returned to background levels within the following 24 hours. ...

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Metabolism/Metabolites
Metabolism is limited, with a hydroxylation rate of up to 5%.
The metabolic pathway was determined in male and female rats and mice after a single oral administration of 1 or 100 mg/kg of [(14)C]-2-(4-methylsulfonyl-2-nitrobenzoyl)-1,3-cyclohexanedione (mesotrione); in rats, the metabolic pathway was determined after 14 consecutive oral administrations of 1 mg/kg mesotrione; and in surgically prepared rats with bile duct cannulation, the metabolic pathway was determined after a single oral administration of 50 mg/kg mesotrione. ...Mesotrione is widely absorbed in rats and mice and rapidly excreted in the urine. ...The main metabolic pathway is the hydroxylation of aromatic rings.

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Biological half-life
...The plasma half-life is approximately 1 hour...

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Mesotrione is rapidly and extensively absorbed after oral administration in rats and mice (absorption: 62-68% within 48 hours). Cmax occurs at approximately 0.5 hours post-dose. The compound has a half-life of 1 hour in human plasma. It undergoes extensive metabolism, primarily via reduction of the triketone moiety and conjugation. In plants, mesotrione is rapidly metabolized in tolerant crops like maize, contributing to its selectivity. Storage: Powder at -20degC (stable for 3 years). In solution at -80degC (stable for 1 year). The compound is soluble in DMSO (250 mg/mL).

Toxicity Summary
Identification and Uses: Methionol is a pale yellow solid with a slightly pleasant odor. Methionol is a herbicide used for field corn, seed corn, sweet corn, yellow popcorn, and sorghum. It is registered for use in the United States, but its approved pesticide uses may change periodically; therefore, it is essential to consult federal, state, and local authorities for information on currently approved uses. Human Exposure and Toxicity: Information regarding the effects of methionol on humans is currently limited. Following administration of methionol to volunteers, plasma tyrosine concentrations increased, peaking at approximately 300 nmol/mL at a dose of 4 mg/kg body weight. Concentrations returned to baseline levels within 2 days of administration. Urinary excretion of tyrosine metabolites increased within 24 hours of administration of a 4 mg/kg dose, but returned to baseline levels within the following 24 hours. Therefore, the mild and transient effects of methionol minimize the likelihood of clinical symptoms arising from systemic exposure during occupational exposure. Methionol is unlikely to be carcinogenic to humans. Animal Studies: In animals, mesotrione is a mild eye irritant but not a skin irritant or sensitizer. In subchronic and chronic oral studies, the main adverse reactions in rats, mice, and dogs were eye damage, hepatic and renal impairment, and/or weight loss. In chronic and reproductive studies, elevated plasma tyrosine levels were observed in rats, mice, and dogs. The eye, hepatic, and renal impairments are thought to be due to elevated blood tyrosine levels caused by inhibition of 4-hydroxyphenylpyruvate dioxygenase. In acute and subchronic neurotoxicity studies in rats, no neuropathological evidence was found. However, sciatic nerve demyelination was associated with elevated plasma tyrosine concentrations in chronic rat studies. In a two-year rat study, an increased incidence of thyroid adenoma was observed only in female rats in the highest dose group, which was also associated with elevated plasma tyrosine concentrations. In developmental studies in rats, rabbits, and mice, decreased/delayed ossification was observed, but no significant maternal toxicity was observed. Ecotoxicity Studies: Antioxidant stress systems, changes in lipid membrane saturation, and the ability of bacteria to degrade mesotrione were investigated. The results showed that Escherichia coli DH5-α tolerated high doses (10 times the field application rate) of the herbicide and completely degraded mesotrione 3 hours after exposure. Before degradation, bacterial growth rates in the presence of mesotrione were lower than in the control group, indicating that the herbicide is toxic to bacterial cells. Changes in membrane lipid saturation reduced damage caused by reactive oxygen species and may have hindered the entry of exogenous substances into cells, while simultaneously activating glutathione S-transferase.

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Toxicity Data
LC50 (Rat)> 5,000 mg/m3

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Interactions
…A series of acute, subchronic, and reproductive studies were conducted in rats, including administration of different doses of mesotrione with or without dietary L-tyrosine; and a developmental study in rabbits using both mesotrione and tyrosine to elucidate the role of tyrosine in the pathogenic mechanism. …The incidence and/or severity of these changes correlated with plasma tyrosine concentrations but not with mesotrione concentrations.

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Non-human toxicity values
Dermal LD50 in rats >2000 mg/kg
Oral LD50 in rats >5000 mg/kg

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Mesotrione has low acute toxicity by oral and dermal routes. It is slightly toxic by inhalation and is slightly irritating to eyes and skin. It is not a skin sensitizer. In rats, the oral LD₅0 is >5,000 mg/kg. Dermal LD₅0 is >2,000 mg/kg. No significant adverse effects are observed at the recommended agricultural use rates. However, as a herbicide, it should be handled with appropriate precautions to avoid excessive exposure. Chronic toxicity studies in laboratory animals have been conducted for regulatory purposes. The US EPA has classified mesotrione as “not likely to be carcinogenic to humans” at doses relevant to human exposure. It is a registered pesticide for agricultural use under the product name Callisto®.

[1]. Mesotrione: A New Selective Herbicide for Use in Maize.Pest Manag Sci.2001 Feb;57(2):120-8.

[2]. CLH report.Proposal for Harmonised Classification and Labelling.Based on Regulation (EC) No 1272/2008 (CLP Regulation), Annex VI, Part 2.Substance Name: Mesotrione.

Mesotrione is an aromatic ketone with the structure cyclohexyl-1,3-dione, where a hydrogen atom at the 2-position is replaced by a 4-(methanesulfonyl)-2-nitrobenzoyl group. It is a herbicide, EC 1.13.11.27 (4-hydroxyphenylpyruvate dioxygenase) inhibitor, exogenous substance, environmental pollutant, and carotenoid biosynthesis inhibitor. It is a sulfone compound, a C-nitro compound, an aromatic ketone, and a β-trione. Its structure is similar to benzophenone. Mechanism of Action: Mesotrione's toxicity is primarily attributed to increased plasma tyrosine levels following 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibition. Due to differences in enzyme activity in the tyrosine catabolism pathway, the increase in tyrosine levels is greater in rats (especially male rats). Studies have shown that mouse models are better predictors of human responses. Human volunteer studies (single oral dose) showed a no-observed-adverse-effect level (NOAEL) of 0.5 mg/kg body weight.

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Mesotrione is a registered herbicide for use in corn (maize) and other crops. It is commercially available under various trade names including Callisto® and Tenacity®. The compound was first described in 2001 and has since become a widely used herbicide globally. Its selectivity for maize is due to rapid metabolism by maize plants and relative tolerance by the crop. Mesotrione has been studied as a potential tool for herbicide resistance management and has been the subject of research on novel HPPD inhibitors. It also serves as a reference compound (IC₅0 ~0.2-0.35 microM against AtHPPD) for the development of new HPPD-inhibiting herbicides. It should not be used for therapeutic purposes in humans.

C14H13NO7S

339.32

339.041

104206-82-8

175967

White to off-white solid powder

1.5±0.1 g/cm3

643.3±55.0 °C at 760 mmHg

165 °C

342.9±31.5 °C

0.0±1.9 mmHg at 25°C

1.583

-0.7

0

7

3

23

627

0

CS(=O)(=O)C1=CC(=C(C=C1)C(=O)C2C(=O)CCCC2=O)[N+](=O)[O-]

KPUREKXXPHOJQT-UHFFFAOYSA-N

InChI=1S/C14H13NO7S/c1-23(21,22)8-5-6-9(10(7-8)15(19)20)14(18)13-11(16)3-2-4-12(13)17/h5-7,13H,2-4H2,1H3

2-(4-methylsulfonyl-2-nitrobenzoyl)cyclohexane-1,3-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: 100 mg/mL (294.71 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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