Disease relevance of ethoxyquin

• Fischer 344 rats readily develop liver cancer when exposed to aflatoxin B1 (AFB1) but dietary administration of the antioxidant ethoxyquin (EQ) provides protection against hepatocarcinogenesis [1].
• The incidences of mammary tumors, carcinomas and fibroadenomas in DMBA-treated animals were reduced by diet containing BHA or ethoxyquin [2].
• Removal of ethoxyquin from the diet after 19 weeks of feeding resulted in a rapid onset of myopathy [3].
• However, ethoxyquin was as effective as vitamin E in maintaining body weight, testes weight, pigmentation of the incisors and in preventing myopathy, observed either histologically or by an elevation in plasma glutamic oxalacetic transaminase (GOT) activity [3].
• Quantitative values for papillomas were also significantly increased except in the ethoxyquin-treated group [4].

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

• Ciprofibrate and ethoxyquin either alone or in combination produced marked hepatomegaly and a significant increase in DNA synthesis as demonstrated by [3H]thymidine incorporation and autoradiographic studies [9].
• In addition, nephrocalcinosis was identified only in the kidneys of rats given EQ after MNNG treatment [10].
• The present study investigated the ability of the structurally different antioxidants, ethoxyquin (ETX) and nordihydroguaiaretic acid (NDGA), to also ameliorate HU developmental toxicity [11].
• Effect of ethoxyquin on the toxicity of the pyrrolizidine alkaloid monocrotaline and on hepatic drug metabolism in mice [12].
• Although the offending allergen was identified in this patient, it proved difficult to find ethoxyquin-free chicken feed products and the patient's dermatitis persisted [13].

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

• 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 [21].
• Inhibitory effect of antioxidants ethoxyquin and 2(3)-tert-butyl-4-hydroxyanisole on hepatic tumorigenesis in rats fed ciprofibrate, a peroxisome proliferator [18].
• We have previously shown that treatment of rats with the chemoprotector ethoxyquin (EQ) results in a marked increase in expression of the Alpha-class glutathione S-transferase (GST) Yc2 subunit which has high activity towards AFB1-8,9-epoxide [Hayes, Judah, McLellan, Kerr, Peacock and Neal (1991) Biochem. J. 279, 385-398] [22].
• Glutathione synthetase was induced approximately 1.5-fold by coumarin, alpha-angelicalactone, ellagic acid and ethoxyquin [23].
• Particularly because of their ability to induce the detoxifying activities of glutathione S-transferase Yc2 and aldehyde reductase, butylated hydroxytoluene, ethoxyquin, indole-3-carbinol, oltipraz, phenethyl isothiocyanate and sinigrin will be effective blocking agents in rodents, if administered prior to AFB1 [24].

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

• When weanling rats were exposed to ethoxyquin (EQ), the conversion of 2N nuclei to 4N and 8N nuclei as measured by flow cytometry was slowed down [16].
• Application of electrochemical detection to the determination of ethoxyquin residues by high-performance liquid chromatography [30].
• Nondestructive distinction between aflatoxin B1 and ethoxyquin in thin-layer chromatography [31].
• Quantitative determination of ethoxyquin in apples by gas chromatography [32].
• Silver staining and densitometric analysis of isoelectric-focused, affinity-purified GST proteins revealed increased expression of two basic GST-like isoforms in ethoxyquin-treated fish [33].

References