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
This study conducted a feeding trial on dairy cows to determine whether Ethoxyquin or its residues would be transferred from the feed to the milk when added at 0.015% of the dry matter intake. The Ethoxyquin content detected in the milk by fluorescence and thin-layer chromatography was less than 7 μg/L. (14) C-Ethoxyquin was distributed in most tissues and blood in rats 0.5 hours after administration. The highest radioactivity was observed in the liver, kidneys, gastrointestinal tract, and adipose tissue throughout the experiment. No activity was observed in the central nervous system. 2.2% and 0.2% of the ingested dose in rats were detected in the liver at 0.5 hours and 6 days after administration, respectively. The peak radioactivity in the liver was measured at 8 hours; 7.5% radioactive material remained in the liver after 6 days. Ethoxyquin and its metabolites were detected in the renal cortex, intestines, lungs, various adipose tissues, and blood of rats 6 days after administration. This compound is readily absorbed and metabolized, and excreted in urine and feces. High-performance liquid chromatography-fluorescence assay (HPLC-FISA) was used to determine the residual levels of Ethoxyquin in mouse tissues. Mice were fed powdered diets containing 0%, 0.125%, and 0.5% Ethoxyquin hydrochloride, respectively, and the residual levels of Ethoxyquin in liver, kidney, lung, and brain tissues were measured at 2, 4, 6, 10, and 14 weeks (n=4 mice per group). Tissue samples were homogenized in 10 volumes (w/v) of acetonitrile-water (7:3 v/v), centrifuged, and the supernatant was frozen for 2–3 hours or until separation, followed by analysis of the supernatant. The mean residual levels of Ethoxyquin in liver ranged from 0.84 to 4.58 μg/g, and in brain tissue from 0.11 to 0.92 μg/g. Mice treated with Ethoxyquin had significantly higher relative liver weight (5.21–7.07% of body weight) and liver glutathione levels (5.99–7.83 uM GSH/g tissue) than the control group (4.67–5.05% of body weight and 4.30–5.78 uM GSH/g tissue, respectively). After 14 weeks of dietary Ethoxyquin supplementation, the mean liver mitochondrial glutathione level (1.68 nM GSH/mg protein) in the high-dose Ethoxyquin feeding group was approximately twice that of the control group and the low-dose Ethoxyquin feeding group (0.83 nM GSH/mg protein and 0.74 nM GSH/mg protein, respectively). Metabolism/Metabolites: The main metabolic reaction was the deethylation of Ethoxyquin, producing 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline and 2,2,4-trimethyl-6-quinoline. Other reactions include hydroxylation, generating four different hydroxylated metabolites and one dihydroxylated metabolite. Following intragastric instillation of (14) C-Ethoxyquin into bile-tubed rats, the average recovered radioactive dose in bile was 28% and 36% at 12 and 24 hours, respectively. The radioactive substances in the bile, in addition to unmetabolized Ethoxyquin, included: 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
Intraperitoneal or oral administration of Ethoxyquin increased epoxide hydratase activity in mice. Concurrent administration of cyclohexylimide prevented this increase. In rats, a single oral administration of Ethoxyquin (200 mg/kg) one hour later showed that in vitro experiments inhibited hepatic microsomal hydroxylation of thiabendazole, aniline, and biphenyl by 65%, 40%, and 40%, respectively. Oral administration of Ethoxyquin (400 mg/kg) delayed the absorption of thiabendazole and reduced its plasma concentration. This study investigated the effects of dietary Ethoxyquin supplementation on aflatoxin B1 metabolism, DNA adduct formation and clearance, and liver tumorigenesis in male Fischer rats. Rats were fed a semi-purified diet containing 0.4% Ethoxyquin for one week, followed by gavage administration of 250 μg/kg aflatoxin B1 five times weekly for two weeks, and were fed a control diet one week after drug withdrawal. Four months later, focal areas of hepatocellular lesions were identified and quantified by staining liver sections with gamma-glutamyl transferase (GGT). Ethoxyquine treatment reduced the area and volume of GGT-positive lesions in the liver by more than 95%. Using the same multiple-dose regimen, the covalent modification pattern of aflatoxin B1 on DNA was determined. Ethoxyquine significantly reduced the binding of aflatoxin B1 to liver DNA: an initial 18-fold reduction and a 3-fold reduction at the end of the treatment period. Although binding was still detectable at 3 and 4 months post-treatment, no effect of ethoxyquine was observed, indicating that these persistent adducts are not primarily associated with the carcinogenic effects of aflatoxin B1. High-performance liquid chromatography (HPLC) analysis of nucleic acid bases showed no qualitative differences in the types of adducts among the treatment groups. The inhibitory effect of ethoxyquine on aflatoxin B1 binding to DNA and tumorigenesis appears to be related to the induction of detoxification enzymes. In rats fed 0.4% ethoxyquin for 7 days, the specific activity of glutathione S-transferase (GST) in hepatic cytoplasm increased fivefold. Multiple molecular forms of glutathione S-transferase were induced, and the level of messenger RNA encoding glutathione S-transferase subunit synthesis was also correspondingly increased. Correspondingly, within 2 hours after oral administration of 250 μg/kg aflatoxin B1, the clearance of aflatoxin B1-glutathione conjugates in the bile of ethoxyquin-fed animals increased 4.5-fold. Therefore, ethoxyquin-induced elimination of enzymes crucial for aflatoxin B1 detoxification (such as glutathione S-transferases) can lead to enhanced carcinogen elimination, the formation of aflatoxin B1-DNA adducts, and subsequent expression of precancerous lesions, ultimately resulting in tumorigenesis.

[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 transparent, pale yellow to dark brown viscous liquid that is easily discolored and stained, and has a thiol-like odor. (NTP, 1992)
Ethoxyquin is a quinoline compound belonging to the 1,2-dihydroquinoline family, with three methyl substituents at positions 2, 2, and 4, and one ethoxy substituent at position 6. It can be used as a herbicide, UDP-glucuronyl transferase activator, neuroprotective agent, Hsp90 inhibitor, genotoxin, food antioxidant, anti-aging agent, and antifungal pesticide. It belongs to the quinoline class of compounds and is also an aromatic ether.
Ethoxyquin is an antioxidant used in animal feed and for color retention in the production of paprika, sweet pepper powder, and pepper flakes. Ethoxyquin was once used as an agricultural insecticide/herbicide but has now been replaced by other pesticides. It is also used as a postharvest soaking solution for apples and pears to prevent scalding.
Antioxidant; also used as a postharvest soaking solution for apples and pears to prevent scalding.

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Therapeutic Uses
(Veterinary): Ethoxyquin is added to animal feed at a concentration of 0.015% as an antioxidant… to help prevent cerebral softening in growing chickens.
(Veterinary): SANTOQUIN has been successfully used in combination with vitamin E to treat white muscle disease in lambs.
Vitamin E, as well as several synthetic antioxidants, such as… ethoxyquin, have altered the tumor-inducing effects of certain carcinogens in multiple target organs. However, the inhibitory effect is achieved at high doses, and synthetic antioxidants at high doses can also induce biotransformation enzymes; therefore, the inhibitory effect may not be entirely attributable to antioxidant activity.

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.)