Disease relevance of nchembio791-comp3

• METHODS: Hepatic hyperplasia was induced in male rats by a diet containing DEHP and clofibrate for 3-60 days [1].
• Finally, CSB(-/-) but not CSA(-/-) mice fed with food containing di(2-ethylhexyl)phthalate (causing elevated levels of oxidative DNA damage in the liver) show weight reduction [2].
• Di(2-ethylhexyl)phthalate (DEHP) is a widely used plasticizer which has been reported to induce a statistically significant increase in the incidence of hepatocellular carcinomas in female Fischer-344 rats (8/50) when administered in the diet at 12 000 p.p.m. for two years [3].
• [4-Chloro-6-(2,3-xylidino)-2-pyrimidyl-thio]acetic acid (Wy-14,643) at 0.1% in the diet produced a much higher incidence of hepatic cancer in male rats than 1.2% di(2-ethylhexyl)phthalate (DEHP) in the diet [4].
• However, the plasticizer di(2-ethylhexyl)phthalate (DEHP), whose toxicity in humans is still undefined, is known to leach from the plastic into stored blood [5].

High impact information on nchembio791-comp3

• Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rats [6].
• Phosphorylation of specific rat plasma membrane proteins during promotion of gamma-glutamyl transpeptidase-positive hepatic foci and inhibition by di(2-ethylhexyl)phthalate [7].
• N-Nitrosodimethylamine, N-nitrosomorpholine, the pesticide Aminocarb, and di(2-ethylhexyl)phthalate were not activated to mutagenic products by the ram seminal vesicle microsomal fraction [8].
• Morphometric analysis of transplanted hepatocytes showed a ninefold and fivefold increase in the volume density of peroxisomes in ciprofibrate and DEHP-fed rats, respectively [9].
• Role of oxidative stress in germ cell apoptosis induced by di(2-ethylhexyl)phthalate [10].

Chemical compound and disease context of nchembio791-comp3

• BACKGROUND & AIMS: We showed previously that the peroxisome proliferators di(2-ethylhexyl)phthalate (DEHP), clofibrate, and 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hydroxyl)acetamide (BR931) alter hepatic sex steroid metabolism and receptor expression during induction of hepatic hyperplasia and hepatocellular carcinoma (HCC) in rats [1].
• Exposure to a common phthalate, di(2-ethylhexyl)phthalate (DEHP), is associated with liver hyperplasia prior to the development of hepatocellular carcinoma in rodents [11].
• Investigation of human and mouse PPARgamma revealed the transcriptional activity of this receptor to be stimulated by mono(2-ethylhexyl)phthalate, a DEHP metabolite that induces developmental and reproductive organ toxicities in rodents [12].
• Non-mutagenicity of 4 metabolites of di(2-ethylhexyl)phthalate (DEHP) and 3 structurally related derivatives of di(2-ethylhexyl)adipate (DEHA) in the Salmonella mutagenicity assay [13].
• Modulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in F344 rats by di(2-ethylhexyl)phthalate [14].

Biological context of nchembio791-comp3

• Di(2-ethylhexyl)phthalate (DEHP) is a peroxisome proliferator that was hepatocarcinogenic in female rats in a National Toxicology Program 2-year bioassay [15].
• The transformation frequency by DEHP was enhanced by exogenous metabolic activation using rat liver postmitochondrial supernatants [16].
• Western and Northern blot analyses showed that MTE-I is constitutively expressed in heart and is strongly induced in liver by feeding rats with di(2-ethylhexyl)phthalate, a peroxisome proliferator, suggesting a role for the enzyme in lipid metabolism [17].
• To examine possible mechanisms for DEHP-associated cancer, we have measured induction of morphological transformation, chromosome aberrations and peroxisome proliferations of cultured Syrian hamster embryo (SHE) cells by DEHP and other peroxisome proliferators [16].
• Dysregulation of ornithine decarboxylase activity, apoptosis and Bcl-2 oncoprotein in Syrian hamster embryo cells stage-exposed to di(2-ethylhexyl)phthalate and tetradecanoylphorbol acetate [18].

Anatomical context of nchembio791-comp3

• We have previously reported that long chain acyl-CoA thioesterase activity was induced about 10-fold in rat liver mitochondria, when treating rats with the peroxisome proliferator di(2-ethylhexyl)phthalate (Wilcke M., and Alexson S. E. H (1994) Eur. J. Biochem. 222, 803-811) [19].
• The phorbol ester TPA and di(2-ethylhexyl)phthalate blocked intercellular communication in all the cell lines tested, but expression of CYP1A1 enzyme reduced the inhibitory activity in these cells [20].
• Induction of peroxisomes and mitochondria by di(2-ethylhexyl)phthalate [21].
• Messenger RNA for 3-hydroxyacyl-CoA dehydrogenase, a mitochondrial matrix enzyme of fatty acid beta-oxidation, was purified from livers of di(2-ethylhexyl)phthalate-treated rats by immunoadsorption of hepatic free polysomes to fixed cells of Staphylococcus aureus and enrichment for poly(A)-rich RNA by oligo(dT)-cellulose chromatography [22].
• Genotoxicity studies of di(2-ethylhexyl)phthalate and its metabolites in CHO cells [23].

Associations of nchembio791-comp3 with other chemical compounds

• The hepatocarcinogenicity of di(2-ethylhexyl)phthalate (DEHP) was demonstrated in a recent bioassay in both rats and mice [24].
• Selenium metabolism in isolated hepatocytes: inhibition of incorporation in proteins by mono(2-ethylhexyl)phthalate, a metabolite of the peroxisome proliferator di(2-ethylhexyl)phthalate [25].
• Several hepatic peroxisome proliferators (HHPs) such as di(2-ethylhexyl)phthalate (DEHP), mono(2-ethylhexyl)-phthalate, clofibrate and tiadenol, induce morphological transformation of Syrian hamster embryo (SHE) cells in vitro [26].
• Male F344 rats and female B6C3F1 mice were treated for 14 days with di(2-ethylhexyl)phthalate (DEHP) or di(2-ethylhexyl)adipate (DEHA), industrial plasticizers, or nafenopin, a hypolipidemic drug [27].
• Hepatocyte expression of tumor associated aldehyde dehydrogenase (ALDH-3) and p21 Ras following diethylnitrosamine (DEN) initiation and chronic exposure to di(2-ethylhexyl)phthalate (DHEP) [28].

Gene context of nchembio791-comp3

• Overexpression of the peroxisome proliferator activated receptor alpha or the human c-Ha-ras transgene is not involved in tumorigenesis induced by di(2-ethylhexyl)phthalate in rasH2 mice [29].
• Co-localized expression of FasL, Fas, Caspase-3 and apoptotic DNA fragmentation in mouse testis after oral exposure to di(2-ethylhexyl)phthalate [30].
• Previously we found a depression in the activity of hepatic xanthine dehydrogenase in rats fed clofibrate or di(2-ethylhexyl)phthalate [31].
• Assessment of carcinogenicity of di(2-ethylhexyl)phthalate in a short-term assay using Xpa-/- and Xpa-/-/p53+/- mice [32].
• In this study, liver mitochondrial AceCS activity, but not heart AceCS2, was greatly induced in di(2-ethylhexyl)phthalate (DEHP)-treated rats [33].

Analytical, diagnostic and therapeutic context of nchembio791-comp3

• Exposure to di(2-ethylhexyl)phthalate in infants receiving extracorporeal membrane oxygenation [34].
• After treatment of rats with di(2-ethylhexyl)phthalate (DEHP) a dose-dependent induction of lauric acid omega-hydroxylase activities, levels of cytochrome P450 4A1 and peroxisomal fatty acid beta-oxidation was found [35].
• Donor exposure to the plasticizer di(2-ethylhexyl)phthalate during plateletpheresis [36].
• Di(2-ethylhexyl)phthalate exposure of apheresis donors is procedure-related [37].
• In all adult patients the levels of di(2-ethylhexyl)phthalate increased tenfold by the end of cardiopulmonary bypass, whereas the levels of mono(2-ethylhexyl)phthalate increased ninefold [38].

References