In four distinct breast cancer cell lines, paclitaxel (PTX) can promote cell death without being hindered by ethoxyquin (EQ). The findings demonstrated that the neuroprotective effect of ethoxyquin (EQ) was only lost when Hsp90 levels were downregulated [2]. According to studies, the ideal concentration range for ethoxyquin's neuroprotective effects is between 30 and 300 nM. It's interesting to note that ethoxyquin loses its neuroprotective effect at higher concentrations (μM) and does not offer additional neuroprotection [3].

Neuroprotection is dose-dependent with ethoxyquin (EQ). The effectiveness of Ethoxyquin peaked at 75 μg/kg, despite the fact that all three doses offered some neuroprotection against a decline in intraepidermal nerve fiber density [2]. As would be expected under normal physiological conditions, rats treated with ethoxyquin (EQ) alone or in a control vehicle gained weight [3].

Absorption, Distribution and Excretion
FEEDING TRIAL IN COWS WAS CONDUCTED TO DETERMINE WHETHER ETHOXYQUIN OR ITS RESIDUES ARE TRANSFERRED FROM FEED TO MILK WHEN ADDED TO COW FEED AT 0.015% OF DRY MATTER INTAKE. LESS THAN 7 UG ETHOXYQUIN/L WAS DETECTED IN MILK BY FLUORIMETRY & BY THIN-LAYER CHROMATOGRAPHY.
(14)C-ETHOXYQUIN WAS DISTRIBUTED THROUGHOUT MOST TISSUES & BLOOD AT 0.5 HR AFTER ADMIN TO RATS. HIGHEST RADIOACTIVITY THROUGHOUT EXPERIMENT WAS OBSERVED IN LIVER, KIDNEY, GI TRACT & ADIPOSE TISSUE. THERE WAS NO ACTIVITY IN CNS. OF DOSE INGESTED BY RAT 2.2 & 0.2% WERE FOUND IN LIVER AT 0.5 HR & 6 DAYS RESPECTIVELY FOLLOWING DOSE. HEPATIC PEAK IN RADIOACTIVITY WAS MEASURED AT 8 HR; & AFTER 6 DAYS 7.5% OF THIS LEVEL WAS STILL PRESENT IN LIVER. 6 DAYS AFTER ADMIN TO RATS RESIDUES OF ETHOXYQUIN & METABOLITES WERE PRESENT IN KIDNEY CORTEX, INTESTINES, LUNG, VARIOUS ADIPOSE TISSUES & BLOOD.
The compound is readily absorbed, metabolized, and excreted in urine and feces.
Ethoxyquin residue levels in the mouse tissue were determined by the HPLC-fluorometric detection method. Mice were given powdered feed containing 0, 0.125, and 0.5% ethoxyquin hydrochloric acid and the ethoxyquin residue levels in liver kidney, lung, and brain tissues were determined after 2, 4, 6, 10, and 14 wk (4 mice/group). The tissue samples were homogenized in 10 volumes (w/v) of acetonitrile-water (7:3 v/v) centrifuged and the supernatants were stored in a freezer for 2-3 hr or until the two layers separated; then the clear upper layers were analyzed. The mean ethoxyquin residue levels in the tissue ranged 0.84-4.58 ug ethoxyquin/g liver and 0.11-0.92 ug ethoxyquin/g brain. The relative weight of the liver (5.21-7.07% body weight) and the hepatic glutathione level (5.99-7.83 uM GSH/g tissue) of mice that received ethoxyquin were significantly higher than those of the controls (4.67-5.05% body weight and 4.30-5.78 uM GSH/g tissue, respectively). The mean hepatic mitochondrial glutathione levels of the higher ethoxyquin feeding group following dietary administration of ethoxyquin for 14 wk, was approximately twofold (1.68 nM GSH/mg protein) of both the control and the lower ethoxyquin feeding groups (0.83 and 0.74 nM GSH/mg protein, respectively.

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Metabolism / Metabolites
MAJOR METABOLIC REACTION WAS DEETHYLATION OF ETHOXYQUIN WHICH PRODUCED 6-HYDROXY-2,2,4-TRIMETHYL-1,2-DIHYDROQUINOLINE & 2,2,4-TRIMETHYL-6-QUINOLINE. OTHER REACTIONS WERE HYDROXYLATION TO FOUR DIFFERENT HYDROXYLATED METABOLITES & ONE DIHYDROXYLATED METABOLITE.
An avg of 28 & 36% of dose of radioactivity was recovered in bile in 12 & 24 hr respectively following intragastric admin of (14)C-ethoxyquin to bile duct cannulated rats. Biliary radioactive substances included, in addn to unchanged ethoxyquin...8-hydroxyethoxyquin; hydroxylated 8-hydroxyethoxyquin; 6-ethoxy-2,2,4-trimethylquinolone; hydroxylated 6-ethoxy-2,2,4-trimethyl-8-quinolone; 6-ethoxy-2,4-dimethylquinoline; and 2,2,4-trimethyl-6-quinolone.

Interactions
ELEVATION OF EPOXIDE HYDRATASE ACTIVITY IS OBTAINED BY IP OR ORAL TREATMENT OF MICE WITH ETHOXYQUIN. THIS ELEVATION IS PREVENTED BY CONCOMITANT TREATMENT WITH CYCLOHEXIMIDE.
SINGLE ORAL DOSE OF ETHOXYQUIN (200 MG/KG) TO RATS INHIBITED HEPATIC MICROSOMAL HYDROXYLATION OF THIABENDAZOLE, ANILINE & BIPHENYL BY 65, 40 & 40% IN VITRO AT 1 HR AFTER DOSAGE. ORAL ETHOXYQUIN (400 MG/KG) DELAYED ABSORPTION OF & DECR PLASMA CONCN OF THIABENDAZOLE.
The effects of dietary administration of ethoxyquin on aflatoxin B1 metabolism, DNA adduct formation and removal and hepatic tumorigenesis were examined in male Fischer rats. Rats were fed a semipurified diet containing 0.4% ethoxyquin for 1 wk, gavaged with 250 ug of aflatoxin B1 per kg 5 times a wk during the next 2 wk, and finally restored to the control diet 1 wk after cessation of dosing. At 4 mo, focal areas of hepatocellular alteration were identified and quantitated by staining sections of liver for gamma-glutamyl transpeptidase. Treatment with ethoxyquin reduced by greater than 95% both area and volume of liver occupied by gamma-glutamyl transpeptidase-positive foci. Utilizing the same multiple dosing protocol, patterns of covalent modifications of DNA by aflatoxin B1 were determined. Ethoxyquin produced a dramatic reduction in the binding of aflatoxin B1 to hepatic DNA: 18-fold initially and 3-fold at the end of the dosing period. Although binding was detectable at 3 and 4 mo postdosing, no effect of ethoxyquin was observed, suggesting that these persistent adducts are not of primary relevance to aflatoxin B1 carcinogenesis. Analysis of nucleic acid bases by high-performance liquid chromatography revealed no qualitative differences in adduct species between treatment groups. The inhibitory effect of ethoxyquin on aflatoxin B1 binding to DNA and tumorigenesis appears related to induction of detoxication enzymes. Rats fed 0.4% ethoxyquin for 7 days showed a 5-fold increase in hepatic cytosolic glutathione S-transferase (GST)-specific activities. Multiple molecular forms of glutathione S-transferase were induced, and concomitant elevations in messenger RNA levels coding for the synthesis of glutathione S-transferase subunits were observed. Correspondingly, billary elimination of aflatoxin B1-glutathione conjugate was increased 4.5-fold in animals on the ethoxyquin diet during the first 2 hr following oral administration of 250 micrograms of aflatoxin B1 per kg. Thus, induction by ethoxyquin of enzymes important to aflatoxin B1 detoxication, such as glutathione S-transferase can lead to enhanced carcinogen elimination, as well as reductions of aflatoxin B1-DNA adduct formation and subsequent expression of preneoplastic lesions, and, ultimately, neoplasia.

[1]. Development of a high-throughput screening cancer cell-based luciferase refolding assay for identifying Hsp90 inhibitors. Assay Drug Dev Technol. 2013 Oct;11(8):478-88.

[2]. Ethoxyquin prevents chemotherapy-induced neurotoxicity via Hsp90 modulation. Ann Neurol. 2013 Dec;74(6):893-904.

[3]. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity. Sci Rep. 2016 Jun 28;6:28861.

Ethoxyquin is a clear light yellow to dark brown viscous liquid. Discolors and stains badly. Mercaptan-like odor. (NTP, 1992)
Ethoxyquin is a quinoline that is 1,2-dihydroquinoline bearing three methyl substituents at position 2, 2 and 4 as well as an ethoxy substituent at position 6. It has a role as a herbicide, an UDP-glucuronosyltransferase activator, a neuroprotective agent, a Hsp90 inhibitor, a genotoxin, a food antioxidant, a geroprotector and an antifungal agrochemical. It is a member of quinolines and an aromatic ether.
Ethoxyquin is an antioxidant used in animal feeds and for the preservation of colour in the production of chili powder, paprika and ground chilli. Ethoxyquin is formerly used as an agricultural pesticide/herbicide, now superseded. Also used as a post-harvest dip for apples and pears to prevent scald.
Antioxidant; also a post-harvest dip to prevent scald on apples and pears.

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Therapeutic Uses
(VET): Ethoxyquin is added to animal feeds at 0.015% as an antioxidant ... to help prevent encephalomalacia in growing chickens.
(VET): SANTOQUIN HAS BEEN SUCCESSFULLY USED WITH VITAMIN E IN TREATMENT OF WHITE MUSCLE DISEASE IN LAMBS.
Vitamin E and also several synthetic antioxidants, such as ... ethoxyquin, have modified tumor induction by certain carcinogens in a number of target organs. However, inhibition was achieved at high doses at which induction of biotransformation enzymes also occurs with the synthetics and, therefore, inhibition may not be due solely to antioxidant effects.

C14H19NO

217.31

217.146

91-53-2

63301-91-7

3293

Light yellow to brown liquid

1.0±0.1 g/cm3

333.1±42.0 °C at 760 mmHg

<0ºC

137.8±17.3 °C

0.0±0.7 mmHg at 25°C

1.512

3.93

1

2

2

16

283

0

O(CC)C1C=C2C(NC(C)(C)C=C2C)=CC=1

DECIPOUIJURFOJ-UHFFFAOYSA-N

InChI=1S/C14H19NO/c1-5-16-11-6-7-13-12(8-11)10(2)9-14(3,4)15-13/h6-9,15H,5H2,1-4H3

6-ethoxy-2,2,4-trimethyl-1H-quinoline

HSDB 400; EMQ; Amea 100

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 : ≥ 50 mg/mL (~230.09 mM)
H2O : < 0.1 mg/mL

Solubility in Formulation 1: ≥ 3.5 mg/mL (16.11 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 35.0 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: ≥ 3.5 mg/mL (16.11 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 35.0 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: ≥ 3.5 mg/mL (16.11 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 35.0 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.)