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Chemical Compound Review

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

Synonyms: Ethoxychin, Niflex, Santoquine, ethoxyquin, Ethoxyquine, ...
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Disease relevance of ethoxyquin


High impact information on ethoxyquin

  • This particular form of GST is expressed constitutively only at low levels in rats, but it is inducible by antioxidants such as ethoxyquin, and it accounts for much of the chemoprotective effects of a variety of substances, including natural dietary components that putatively act via an "antioxidant response element" (ARE) [5].
  • We have cloned and sequenced a cDNA encoding an aldehyde reductase (AFB1-AR), which is expressed in rat liver in response to dietary ethoxyquin [6].
  • Protection of liver against the toxic and carcinogenic effects of aflatoxin B1 (AFB1) can be achieved through the induction of detoxification enzymes by chemoprotectors such as the phenolic antioxidant ethoxyquin [6].
  • In rat liver, Afar is strongly inducible by the antioxidants ethoxyquin and butylated hydroxyanisole, which protect the rat against aflatoxin B1-induced liver tumorigenesis by detoxifying its genotoxic and cytotoxic dialdehyde [7].
  • This method has been used to show that, in addition to AFAR, two other rat liver carbonyl-reducing enzymes are induced by ethoxyquin, and that these are distinct from NAD(P)H: quinone oxidoreductase [8].

Chemical compound and disease context of ethoxyquin


Biological context of ethoxyquin

  • Reduction of Prx I expression by small interfering RNA transfection resulted in a significant decrease in p38 MAPK activation, whereas the up-regulation of Prx I expression with either oxLDL or ethoxyquin led to increased p38 MAPK activation [14].
  • Our work using animal models based on the differential effects of ethoxyquin on the kinetics of aflatoxin-DNA adducts and gamma glutamyl transpeptidase-positive foci formation indicate that the direct linear extrapolation of total adduct content in target tissues to dose may be inappropriate to assign risk to people (or rats) [15].
  • EQ is a very potent inducer of gamma-glutamyltranspeptidase (GGT), but expression depended on the age of the animals, the length of treatment time and apparently the ploidy status of the liver [16].
  • It appeared that when EQ was present in the diet, significant numbers of diploid hepatocytes undergoing DNA synthesis also underwent mitosis and cytokinesis giving rise to new diploid hepatocytes [16].
  • Comparison of the deduced amino acid sequence of the mouse Yc polypeptide with the primary structures of the rat Alpha-class GST enzymes revealed that it is more closely related to the ethoxyquin-induced rat liver Yc2 subunit than to the constitutively expressed rat liver Yc1 subunit [17].

Anatomical context of ethoxyquin

  • Accordingly, the effect of synthetic antioxidants 2(3)-tert-butyl-14-hydroxyanisole and ethoxyquin on the peroxisome proliferator 2-[4-(2,2-dichlorocyclopropyl)phenoxy]2-methyl-propionic acid (ciprofibrate)-induced hepatic tumorigenesis has been examined in male Fischer 344 rats [18].
  • The dialdehyde can be detoxified by reduction to a dialcohol through the catalytic actions of an enzyme present in the hepatic cytosol from rats fed EQ-containing diets; this metabolite is essentially undetectable in reaction mixtures that use hepatic cytosol from rats fed control diets [1].
  • In weanling rats treated with EQ for 7 days, > 80% of the hepatocytes expressed GGT, while in 42 day old rats similarly treated < 50% were positive for this enzyme [16].
  • However, AKR7A1 was inducible by the synthetic antioxidant ethoxyquin in liver, kidney, and small intestine, but not in the other tissues examined [19].
  • By using PCR techniques, mRNA III (homologous to both mouse III and IV) and an mRNA (IV) with homology to VI in mouse were found in ethoxyquin- and aflatoxin B1-treated rat liver and kidney as well as in a hepatoma-derived cell line [20].

Associations of ethoxyquin with other chemical compounds


Gene context of ethoxyquin

  • Transfection of the human promoter into ethoxyquin-treated mouse 3T3 cells induces a 3.5-fold increase in promoter activity and a CHOP-C/EBP band appears on gel shifts performed with the 5' probe from the human aldehyde reductase promoter [25].
  • Although evidence suggests that induction of Yc2 is responsible for the high detoxification capacity of livers from ethoxyquin-treated rats for AFB1-8,9-epoxide, resistance towards AFB1 may be multifactorial in this instance as dietary ethoxyquin also induces the Ya1, Ya2 and Yc1 subunits about 2.2-, 10.9- and 2.7-fold respectively [26].
  • Besides its distinct electrophoretic and immunochemical properties, rAFAR2 appears to be regulated differently from rAFAR1 as it is expressed in most rat tissues and does not appear to be induced by ethoxyquin [27].
  • Mrp2 protein levels were significantly increased by all 3 PXR ligands/CYP3A inducers (pregnenolone-16alpha-carbonitrile [PCN], spironolactone [SP], and dexamethasone [DEX]) and by both ARE/EpRE ligands (ethoxyquin [EQ] and oltipraz [OPZ]) [28].
  • Recent studies with ethoxyquin (EQ) have shown that this antioxidant stimulates the formation of a form of cytochrome P 450 which resembles the phenobarbital-inducible type [29].

Analytical, diagnostic and therapeutic context of ethoxyquin


  1. Resistance to aflatoxin B1 is associated with the expression of a novel aldo-keto reductase which has catalytic activity towards a cytotoxic aldehyde-containing metabolite of the toxin. Hayes, J.D., Judah, D.J., Neal, G.E. Cancer Res. (1993) [Pubmed]
  2. Modification by antioxidants and p,p'-diaminodiphenylmethane of 7,12-dimethylbenz[a]anthracene-induced carcinogenesis of the mammary gland and ear duct in CD rats. Hirose, M., Masuda, A., Inoue, T., Fukushima, S., Ito, N. Carcinogenesis (1986) [Pubmed]
  3. Influence of age on the vitamin E requirement for resolution of necrotizing myopathy. Gabriel, E., Machlin, L.J., Filipski, R., Nelson, J. J. Nutr. (1980) [Pubmed]
  4. Summation effects of uracil and other promoters on epithelial lesion development in the F344 rat urinary bladder initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine. de Camargo, J.L., Shirai, T., Kato, T., Asamoto, M., Fukushima, S. Jpn. J. Cancer Res. (1991) [Pubmed]
  5. Mechanisms of aflatoxin carcinogenesis. Eaton, D.L., Gallagher, E.P. Annu. Rev. Pharmacol. Toxicol. (1994) [Pubmed]
  6. An ethoxyquin-inducible aldehyde reductase from rat liver that metabolizes aflatoxin B1 defines a subfamily of aldo-keto reductases. Ellis, E.M., Judah, D.J., Neal, G.E., Hayes, J.D. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  7. Cloning of the human aflatoxin B1-aldehyde reductase gene at 1p35-1p36.1 in a region frequently altered in human tumor cells. Praml, C., Savelyeva, L., Perri, P., Schwab, M. Cancer Res. (1998) [Pubmed]
  8. Regulation of carbonyl-reducing enzymes in rat liver by chemoprotectors. Ellis, E.M., Judah, D.J., Neal, G.E., O'Connor, T., Hayes, J.D. Cancer Res. (1996) [Pubmed]
  9. Evaluation of liver cell proliferation during ciprofibrate-induced hepatocarcinogenesis. Yeldandi, A.V., Milano, M., Subbarao, V., Reddy, J.K., Rao, M.S. Cancer Lett. (1989) [Pubmed]
  10. Effects of four antioxidants on N-methyl-N'-nitro-N-nitrosoguanidine initiated gastric tumor development in rats. Takahashi, M., Furukawa, F., Toyoda, K., Sato, H., Hasegawa, R., Hayashi, Y. Cancer Lett. (1986) [Pubmed]
  11. Ethoxyquin and nordihydroguaiaretic acid reduce hydroxyurea developmental toxicity. DeSesso, J.M., Goeringer, G.C. Reprod. Toxicol. (1990) [Pubmed]
  12. Effect of ethoxyquin on the toxicity of the pyrrolizidine alkaloid monocrotaline and on hepatic drug metabolism in mice. Miranda, C.L., Carpenter, H.M., Cheeke, P.R., Buhler, D.R. Chem. Biol. Interact. (1981) [Pubmed]
  13. Allergic contact dermatitis to ethoxyquin in a farmer handling chicken feeds. Rubel, D.M., Freeman, S. Australas. J. Dermatol. (1998) [Pubmed]
  14. Dual Role of Peroxiredoxin I in Macrophage-derived Foam Cells. Conway, J.P., Kinter, M. J. Biol. Chem. (2006) [Pubmed]
  15. The use of monoclonal antibody affinity columns for assessing DNA damage and repair following exposure to aflatoxin B1. Groopman, J.D., Kensler, T.W. Pharmacol. Ther. (1987) [Pubmed]
  16. Antioxidants can delay liver cell maturation which in turn affects gamma-glutamyltranspeptidase expression. Davies, R., Edwards, R.E., Green, J.A., Legg, R.F., Snowden, R.T., Manson, M.M. Carcinogenesis (1993) [Pubmed]
  17. Molecular cloning and heterologous expression of a cDNA encoding a mouse glutathione S-transferase Yc subunit possessing high catalytic activity for aflatoxin B1-8,9-epoxide. Hayes, J.D., Judah, D.J., Neal, G.E., Nguyen, T. Biochem. J. (1992) [Pubmed]
  18. Inhibitory effect of antioxidants ethoxyquin and 2(3)-tert-butyl-4-hydroxyanisole on hepatic tumorigenesis in rats fed ciprofibrate, a peroxisome proliferator. Rao, M.S., Lalwani, N.D., Watanabe, T.K., Reddy, J.K. Cancer Res. (1984) [Pubmed]
  19. Expression of rat aldehyde reductase AKR7A1: influence of age and sex and tissue-specific inducibility. Grant, A., Staffas, L., Mancowitz, L., Kelly, V.P., Manson, M.M., DePierre, J.W., Hayes, J.D., Ellis, E.M., Mancowiz, L. Biochem. Pharmacol. (2001) [Pubmed]
  20. Characterization of a promoter for gamma-glutamyl transpeptidase activated in rat liver in response to aflatoxin B1 and ethoxyquin. Griffiths, S.A., Good, V.M., Gordon, L.A., Hudson, E.A., Barrett, M.C., Munks, R.J., Manson, M.M. Mol. Carcinog. (1995) [Pubmed]
  21. Noninhibitory effect of antioxidants ethoxyquin, 2(3)-tert-butyl-4-hydroxyanisole and 3,5-di-tert-butyl-4-hydroxytoluene on hepatic peroxisome proliferation and peroxisomal fatty acid beta-oxidation induced by a hypolipidemic agent in rats. Lalwani, N.D., Reddy, M.K., Qureshi, S.A., Moehle, C.M., Hayashi, H., Reddy, J.K. Cancer Res. (1983) [Pubmed]
  22. Regulation of aflatoxin B1-metabolizing aldehyde reductase and glutathione S-transferase by chemoprotectors. McLellan, L.I., Judah, D.J., Neal, G.E., Hayes, J.D. Biochem. J. (1994) [Pubmed]
  23. Regulation of rat glutamate-cysteine ligase (gamma-glutamylcysteine synthetase) subunits by chemopreventive agents and in aflatoxin B(1)-induced preneoplasia. Shepherd, A.G., Manson, M.M., Ball, H.W., McLellan, L.I. Carcinogenesis (2000) [Pubmed]
  24. Mechanism of action of dietary chemoprotective agents in rat liver: induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism. Manson, M.M., Ball, H.W., Barrett, M.C., Clark, H.L., Judah, D.J., Williamson, G., Neal, G.E. Carcinogenesis (1997) [Pubmed]
  25. Regulation of aldehyde reductase expression by STAF and CHOP. Barski, O.A., Papusha, V.Z., Kunkel, G.R., Gabbay, K.H. Genomics (2004) [Pubmed]
  26. Ethoxyquin-induced resistance to aflatoxin B1 in the rat is associated with the expression of a novel alpha-class glutathione S-transferase subunit, Yc2, which possesses high catalytic activity for aflatoxin B1-8,9-epoxide. Hayes, J.D., Judah, D.J., McLellan, L.I., Kerr, L.A., Peacock, S.D., Neal, G.E. Biochem. J. (1991) [Pubmed]
  27. Purification from rat liver of a novel constitutively expressed member of the aldo-keto reductase 7 family that is widely distributed in extrahepatic tissues. Kelly, V.P., Ireland, L.S., Ellis, E.M., Hayes, J.D. Biochem. J. (2000) [Pubmed]
  28. Regulation of rat multidrug resistance protein 2 by classes of prototypical microsomal enzyme inducers that activate distinct transcription pathways. Johnson, D.R., Klaassen, C.D. Toxicol. Sci. (2002) [Pubmed]
  29. Significance of induction phenomena. Netter, K.J., Kahl, R., Elcombe, C.R. Arch. Toxicol. Suppl. (1978) [Pubmed]
  30. Application of electrochemical detection to the determination of ethoxyquin residues by high-performance liquid chromatography. Olek, M., Declercq, B., Caboche, M., Blanchard, F., Sudraud, G. J. Chromatogr. (1983) [Pubmed]
  31. Nondestructive distinction between aflatoxin B1 and ethoxyquin in thin-layer chromatography. Issaq, H.J., Barr, E.W., Zielinski, W.L. J. Chromatogr. (1977) [Pubmed]
  32. Quantitative determination of ethoxyquin in apples by gas chromatography. Winell, B. The Analyst. (1976) [Pubmed]
  33. Induction of glutathione S-transferase activity and protein expression in brown bullhead (Ameiurus nebulosus) liver by ethoxyquin. Henson, K.L., Stauffer, G., Gallagher, E.P. Toxicol. Sci. (2001) [Pubmed]
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