HCC cell growth is inhibited by demethylcantharidate (0-100 μM; 0, 12, 24, 48, or 72 hours) disodium [1]. Demethylcantharidate (0, 9, 18 or 36 μM; 24 hours) disodium raises Bax/Bcl-2, cleaved caspase-9, and cleaved caspase-3 levels in a dose-dependent manner [1].

The in vivo hepatocellular carcinoma tumorigenesis of SMMC-7721 cells is significantly reduced by demethylcantharidate disodium [1].

Cell Viability Assay[1]
Cell Types: HCC cell lines (SMMC-7721 and Bel-7402)
Tested Concentrations: 0-100 μM
Incubation Duration: 0, 12, 24, 48 or 72 hrs (hours)
Experimental Results: demonstrated anti-proliferative activity in the two HCC cell lines.

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Cell Viability Assay[1]
Cell Types: HCC cells
Tested Concentrations: 0, 9, 18 or 36 µM
Incubation Duration: 24 hrs (hours)
Experimental Results: Induced apoptosis in HCC cells via the intrinsic pathway.

Absorption, Distribution and Excretion
Possibly absorbed through the skin… Following oral administration of a carbon-labeled endogenous herbicide to rats, over 90% of the radioactive material was recovered from feces. The remainder was recovered from urine and exhaled gases. The administered dose was almost completely recovered within 48 hours. When bluegill sunfish were exposed in aquariums to water containing 2 ppm of a carbon-labeled endogenous herbicide, less than 1% of the herbicide was absorbed by the fish. The highest carbon-labeled concentration was found in the viscera and the lowest in the flesh. The endogenous herbicide was also absorbed by the fish through the digestive tract. …Two lactating rats were administered the labeled endogenous herbicide to determine whether it was excreted into their milk. 0.2 mg of the endogenous herbicide (dissolved in a 10% sucrose solution) was administered orally daily for five consecutive days prior to parturition. Postpartum, the mother mice were treated daily for five consecutive days with 0.4 mg of methamidophos dissolved in a 10% sucrose solution. After euthanizing the pups, no radioactivity was detected in any tissue or stomach contents, indicating that methamidophos is not secreted into the milk of lactating mothers.
For more complete data on the absorption, distribution, and excretion of methamidophos (6 species), please visit the HSDB records page.

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Metabolism/Metabolites
This article reviews the metabolic pathways of the widely used herbicide methamidophos in various organisms and systems. Limited research results suggest that methamidophos absorbed by plants and fish is completely metabolized, but in mammals, it is primarily excreted in a bound form.

Interactions
The herbicidal activity of Murbetol, a combination of endothelin and isopropyl phenylcarbamate, is hundreds of times higher than that of either ingredient alone. L1-mediated cell adhesion and neurite growth are inhibited in a dose-dependent manner by ethanol and other small-molecule alcohols. The inhibitory effect of ethanol on L1-mediated adhesion may contribute to fetal alcohol syndrome. Although the pharmacological mechanisms by which ethanol inhibits L1 adhesion are well elucidated and antagonistic molecules have been identified, the cellular mechanisms remain unclear. The identification of ethanol-sensitive and ethanol-insensitive cell lines from the same stable L1 transfection cell line suggests that other cytokines regulate the effects of ethanol. This study investigated the role of intracellular signaling molecules in the inhibition of L1 adhesion by ethanol. L1-mediated function is regulated by phosphorylation events, and several kinases are known to phosphorylate L1, including casein kinase II (CK2), ERK 1/2, and p90rsk. In ethanol-sensitive NIH/3T3 cells (2A2-L1) stably expressing human L1 and in BMP-7-treated NG108 cells, pharmacological inhibition of CK2 activity blocked the inhibitory effect of ethanol on L1 adhesion. However, ethanol had no direct effect on CK2 activity or subunit localization. Next, we investigated the effect of protein phosphatase inhibitors on ethanol sensitivity. Pretreatment of 2A2-L1 cells with okadaic acid and BMP-7-treated NG108 cells significantly reduced the inhibitory effect of ethanol on L1 adhesion in a dose-dependent manner (IC50 = 10 nM). A similar effect was observed with another phosphatase inhibitor, endothelin. In the absence of ethanol, neither drug had any effect on L1 cell adhesion. The necessity of CK2 and phosphatase activity for ethanol sensitivity may stem from the fact that PP2A phosphatase is activated by CK2. Therefore, inhibition of CK2 may also reduce PP2A activity. The fact that ethanol has no direct effect on CK2 activity supports the idea that, in addition to CK2, another protein (PP2A) may be a more direct regulator of L1 cell adhesion sensitivity to ethanol. In summary, these results suggest that the inhibitory effect of ethanol on L1 cell adhesion can be regulated by intracellular signaling pathways and provide new avenues for the development of ethanol antagonists. The beneficial effects of phosphodiesterase 5A inhibitors in ischemia/reperfusion injury and cardiac hypertrophy are well-established. Inhibition of the cardiac Na+/H+ exchanger (NHE-1) also has beneficial effects on these diseases, and studies suggest a possible link between these two treatment strategies. To further understand the intracellular pathways by which phosphodiesterase 5A inhibitors reduce NHE-1 activity, we performed experiments in isolated cat cardiomyocytes. NHE-1 activity was assessed by the rate at which intracellular pH recovered from a sustained acidic load under bicarbonate-free conditions. Inhibition of phosphodiesterase 5A with sildenafil (1 μmol/L) did not affect basal intracellular pH; however, it did reduce proton efflux after acidic loading (J(H); in millimoles/liter/min) (6.97 ± 0.43 in the control group and 3.31 ± 0.58 in the sildenafil group; P < 0.05). The effect of sildenafil was reversed when both protein phosphatases 1 and 2A were simultaneously blocked with 100 nmol/L okadaic acid (proton efflux: 6.77 ± 0.82). Conversely, selective inhibition of protein phosphatases 2A (1 nmol/L okadaic acid or 100 μmol/L endothelin) did not produce the same effect (3.86 ± 1.0 and 2.61 ± 1.2, respectively), suggesting that sildenafil-induced NHE-1 inhibition involves only protein phosphatases 1. Furthermore, sildenafil prevents acidosis-induced increases in NHE-1 phosphorylation without affecting activation of the extracellular signal-regulated kinase 1/2-p90 (RSK) pathway. Our results indicate that during intracellular pH recovery after acid loading, phosphodiesterase 5A inhibitors reduce NHE-1 phosphorylation levels via a protein phosphatase 1-dependent pathway, thereby decreasing NHE-1 activity.

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Non-human toxicity values
Oral LD50 in rats: Acidic (technical grade) 38-51 mg/kg
Oral LD50 in rats: Sodium salt (19.2% solution) 182-197 mg/kg
Oral LD50 in rats: Amino salt (66.7% formulation) 206 mg/kg
Oral LD50 in male rats: 57 mg/kg
For more complete non-human toxicity data for ENDOTHALL (6 items), please visit the HSDB record page.

[1]. Sodium demethylcantharidate induces apoptosis in hepatocellular carcinoma cells via ER stress. Am J Transl Res. 2019;11(5):3150-3158. Published 2019 May 15.

The monohydrate is a colorless, non-corrosive crystal used as a selective herbicide. Endothelin disodium is an organic molecular entity. A porcine pancreatic enzyme preparation whose lipase content has been standardized. See also: pancreatic lipase (note moved to); endothelin disodium (note moved to). Mechanism of Action: Cyclic adenosine monophosphate-dependent protein kinase (PKA) and calmodulin-dependent protein kinase II (CaMKII)-mediated phosphorylation activates histamine synthesis in nerve endings, but the phosphatases that inactivate them have not been studied. This study shows that the protein phosphatase 2A (PP2A)/protein phosphatase 1 (PP1) inhibitor okadaic acid can increase histamine synthesis in rat cortical microprisms containing histaminergic nerve endings by up to two-fold. The PP2A/PP1 inhibitor calicline mimics this effect, but its inactive analogue 1-norokadaicone does not. Other phosphatase inhibitors, such as endofloxacin (PP2A), cypermethrin, and cyclosporine A (protein phosphatase 2B, PP2B), showed much lower effects. The effect of okadaic acid appears to be mediated by activation of histamine synthases—histidine decarboxylase. PKA-mediated activation of histamine synthesis reduced the EC50 value and maximum effect of okadaic acid. On the other hand, CaMKII-mediated activation of histamine synthesis reduced the maximum effect of okadaic acid but increased its EC50 value. In summary, our results indicate that brain histamine synthesis is regulated by phosphatases PP2A and PP1 (and possibly PP2B) as well as protein kinases. ...We investigated the role of PP activity in glial cell detoxification of exogenous hydrogen peroxide (H2O2) using protein phosphatase (PP) inhibitors and primary cultured rat cerebellar glial cells. The marine toxin okadaic acid (OKA) is a potent inhibitor of PP1 and PP2A that causes concentration-dependent degeneration of astrocytes and significantly increases the generation of hydrogen peroxide radicals. Subtoxic concentrations of OKA exposure significantly enhanced the toxicity of exogenous H₂O₂. In the absence of toxins, the estimated H₂O₂ concentration that reduced astrocyte survival by 50% after 3 hours was 720 ± 40 μM; while in the presence of toxins, this concentration was estimated to be 85 ± 30 μM. The peroxidase inhibitors calyculin A and endothall also enhanced the toxicity of H₂O₂ to cerebellar astrocytes. OKA produced time-dependent inhibition of both glial cell catalase and glutathione peroxidase, reducing the activity of these enzymes by approximately 50% after 3 hours, while the activity of other enzymes remained unaffected. Furthermore, OKA reduced the intracellular total glutathione content and increased the content of oxidized glutathione to approximately 25% of total glutathione. OKA-treated astrocytes cleared H₂O₂ from the culture medium approximately twice as slowly as the control group. Our findings indicate that PP activity plays a crucial role in the antioxidant mechanism, protecting astrocytes from H2O2 damage.

C8H8NA2O5

230.13

230.017

129-67-9

Sodium Demethylcantharidate;13114-29-9

8519

White to off-white solid powder

447.8ºC at 760 mmHg

Converted to anhydride at 90 °C
Colorless crystals. MP: 144 °C /Endothall monohydrate/

190.5ºC

2.88E-09mmHg at 25°C

0

5

0

15

224

0

XRHVZWWRFMCBAZ-UHFFFAOYSA-L

InChI=1S/C8H10O5.2Na/c9-7(10)5-3-1-2-4(13-3)6(5)8(11)12;;/h3-6H,1-2H2,(H,9,10)(H,11,12);;/q;2*+1/p-2

disodium;7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylate

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 (e.g. under nitrogen), avoid exposure to moisture and light.

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

H2O : 33.33 mg/mL (144.83 mM)
DMSO : < 1 mg/mL

Solubility in Formulation 1: 50 mg/mL (217.27 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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