Target: HPPD enzyme[1]

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].

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].

Absorption, Distribution and Excretion
Approximately 70% /mestrione was absorbed/ within 72 hours. /Mestrione was/ widely distributed, highest residues in liver and kidney at 72 hours. No evidence of accumulation. 65-70% excreted within 72 hours, mainly via urine (55%)
NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. ... A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg x kg(-1) body weight of either formulation and the half-life in plasma was approximately 54 hr. There were no statistical differences in mean (+/- s.d.) AUC(0,infinity) (capsule 602 +/- 154 vs solution 602 +/- 146 ug x ml(-1) hr) or t1/2 (capsule 55 +/- 13 vs solution 54 +/- 8 hr) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 hr and was independent of dose and AUC(0,infinity) and Cmax increased linearly with dose. Following administration of 1 mg NTBC x kg(-1) in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol x ml(-1). Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol x ml(-1) following a dose of 4 mg x kg(-1) body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 hr immediately following a dose of 4 mg mesotrione x kg(-1), but returned to background levels during the following 24 hr period. ...

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Metabolism / Metabolites
Limited metabolism, up to 5% metabolized by hydroxylation.
The metabolic fate of [(14)C]-2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione (mesotrione) has been determined in the male and female rat and mouse following a single oral dose of either 1 or 100 mg/kg, in rat given 14 consecutive oral doses of 1 mg/kg, and in the surgically prepared, bile duct-cannulated rat following a single oral dose of 50 mg/kg. ...Mesotrione was extensively absorbed and rapidly excreted via urine in both rat and mouse. ...The major metabolic pathway was hydroxylation of the aromatic ring.

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Biological Half-Life
... The plasma half-life was approximately 1 hr ...

Toxicity Summary
IDENTIFICATION AND USE: Mesotrione is a pale yellow solid with a faint pleasant odor. Mesotrione is an herbicide used on field corn, seed corn, sweet corn, yellow popcorn, and grain sorghum. Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses. HUMAN EXPOSURE AND TOXICITY: Limited information is available on the effects of exposure to mesotrione on humans. Administration of mesotrione to volunteers resulted in an increase in plasma tyrosine concentrations, which reached a maximum of approximately 300 nmol/mL following a dose of 4 mg/kg body weight. Concentrations returned to background levels within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 hr immediately following a dose of 4 mg/kg, but returned to background levels during the following 24 hr period. Thus, the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use. Mesotrione is not likely to be carcinogenic to humans. ANIMAL STUDIES: In animals, mesotrione is a mild eye irritant, but is not a dermal irritant or a dermal sensitizer. In subchronic and chronic oral studies, ocular lesions, liver and kidney effects, and/or body weight decrements were the major adverse effects seen in rat, mouse, and dog. Plasma tyrosine levels were increased in rat, mouse and dog in the chronic and reproduction studies. The ocular, liver and kidney effects are believed to be mediated by high tyrosine levels in the blood caused by inhibition of the enzyme 4-hydroxyphenylpyruvate dioxygenase. No evidence of neuropathology was found in acute and sub-chronic neurotoxicity studies in rat. However, sciatic nerve demyelination in the chronic rat study was associated with increased plasma tyrosine concentration. Increased incidence of thyroid adenomas in female rats only at the highest dose level in the 2 year rat study was also associated with increased plasma tyrosine concentration. Reduced/delayed ossification in rat, rabbit and mouse developmental studies were noted in the absence of overt maternal toxicity. ECOTOXICITY STUDIES: Antioxidative stress systems, saturation changes of lipid membranes, and the capacity of bacteria to degrade mesotrione were examined. The results showed that Escherichia coli DH5-alpha was able to tolerate high doses of the herbicide (10 times field rate), and completely degraded mesotrione after 3 hr of exposure. Growth rates in the presence of mesotrione were lower than in the control, prior to the period of degradation, showing toxic effects of this herbicide on bacterial cells. Changes in the saturation of the membrane lipids reduced the damage caused by reactive oxygen species and possibly hindered the entry of xenobiotics in the cell, while activating glutathione-S-transferase enzyme.

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

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Interactions
... A range of acute, subchronic and reproduction studies in the rat involving administration of different doses of mesotrione, with or without co-administration of dietary L-tyrosine and a developmental study in the rabbit utilising both mesotrione and tyrosine were used to elucidate the role of tyrosine in the pathogenesis of effects. ...The incidence and/or severity of the changes correlated with plasma tyrosine concentrations but not with concentrations of mesotrione.

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Non-Human Toxicity Values
LD50 Rat dermal >2000 mg/kg
LD50 Rat oral >5000 mg/kg

[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 that is cyclohexa-1,3-dione in which one of the hydrogens at position 2 is substituted by a 4-(methanesulfonyl)-2-nitrobenzoyl group. It has a role as a herbicide, an EC 1.13.11.27 (4-hydroxyphenylpyruvate dioxygenase) inhibitor, a xenobiotic, an environmental contaminant and a carotenoid biosynthesis inhibitor. It is a sulfone, a C-nitro compound, an aromatic ketone and a beta-triketone. It is functionally related to a benzophenone.

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Mechanism of Action
Mechanistic studies show that the toxic effects of /mesotrione/ are largely attributable to increased plasma tyrosine levels following 4-hydroxyphenyl pyruvate dioxygenase (HPPD) inhibition. Tyrosine levels are increased to a greater extent in rats (particularly males) due to differences in the activity of enzymes in the tyrosine catabolic pathway. Studies show that the mouse is more predictive of the response in humans. Human volunteer study (single oral dose) shows a NOAEL of 0.5 mg/kg bw.

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

165ºC

342.9±31.5 °C

0.0±1.9 mmHg at 25°C

1.583

-0.7

0

7

3

23

627

0

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.)