Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies suggest that thyroid hormones are involved in the mechanism of peroxisome proliferation. However, those studies utilized either surgically thyroidectomized animals, which are also parathyroidectomized, without calcium supplementation, or animals pretreated with antithyroid drugs, which are known to produce metabolic as well as morphometric changes in the liver. Therefore, these animal models confound conclusions drawn in previous studies. The purpose of the present study was to investigate the role of thyroid hormones in peroxisomal proliferation by the phthalate ester plasticizer, di-(2-ethylhexyl)phthalate (DEHP) in thyroidectomized rats with parathyroid replants. Using this model, it was found that DEHP-induced hepatomegaly was partially dependent on thyroid hormones. DEHP produced a thyromimetic effect, inducing the activity of malic enzyme and carnitine acetyltransferase in the absence of thyroid hormones. Additionally, DEHP-induced activities of catalase were shown to be dependent on thyroid hormones, whereas the thyroid status of the animal had no effect on DEHP-induced activities of the peroxisomal beta-oxidizing enzymes. These data further confirm that endocrine factors play variable roles in the process of induction of various peroxisomal enzymes caused by peroxisome proliferators.
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PMID:Induction of peroxisomal enzyme activities by di-(2-ethylhexyl) phthalate in thyroidectomized rats with parathyroid replants. 146 23

Earlier studies indicated that the hepatocarcinogenic activity of two peroxisome proliferators (PP) Wy-14,643 and di(2-ethylhexyl)phthalate (DEHP) correlated to the degree of lipofuscin accumulation and sustained cell replication rather than the level of peroxisome induction. This study extends the comparison of peroxisome proliferation, lipofuscin accumulation and cell replication responses in rats fed (i) clofibric acid at 5000 p.p.m. (CA), a regimen of moderate hepatocarcinogenicity; (ii) Wy-14,643 at 50 p.p.m. (WYLD), a dose of unknown hepatocarcinogenicity; and (iii) Wy-14,643 at 1000 p.p.m. (WYHD), as the highly hepatocarcinogenic regimen. Adult male F344 rats were fed the experimental diets for 1, 2, 5, 11 or 22 weeks. Relative liver weights (% of body weight) were increased in rats fed CA (1.6- to 1.7-fold), WYHD or WYLD (2.0- to 2.7-fold), compared to controls (approximately 3%) at all time points. All rats fed CA, WYHD or WYLD had similar hepatic peroxisome proliferation at all time points with large elevations in peroxisomal enzyme activities and number, size and mean volume of peroxisomes. In contrast, hepatocytic lipofuscin accumulation differed between treatments, with a decreasing order of accumulation observed in WYHD greater than WYLD approximately equal to CA greater than controls. Replicative DNA synthesis (as assessed by nuclear labeling index, LI) in nonlesion hepatocytes was markedly elevated at 1 week by both WYHD and WYLD (45- and 40-fold over controls respectively) while CA induced a 10-fold response over controls (control LI less than or equal to 1%). From week 2 to week 22 the hepatocytic LI was sustained in WYHD and WYLD rats (8- and 4-fold over controls respectively) but not in CA-rats, as compared to controls. In contrast to the cell replication response, apoptosis was elevated only in WYHD at 22 weeks. Collectively, this study supports the conclusion that neither hepatomegaly nor peroxisome proliferation are accurate predictors of carcinogenic activity for PP. Further, these results suggest that if lipofuscin accumulation or sustained cell turnover are indicators of PP-induced carcinogenesis, then WYLD should be at least as carcinogenic as CA. The moderate carcinogenic activity of CA also suggests that additional factor(s) may be necessary besides lipofuscin accumulation and sustained cell replication to determine the ultimate carcinogenic activity of PP.
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PMID:Contrasting hepatocytic peroxisome proliferation, lipofuscin accumulation and cell turnover for the hepatocarcinogens Wy-14,643 and clofibric acid. 160 Jun 4

The relationship between hepatomegaly and the hepatocarcinogenesis associated with by peroxisome proliferators was examined. (1) Male F-344 rats were maintained on diets containing clofibrate, ciprofibrate, nafenopin, gemfibrozil, Wy-14, 643, di(2-ethylhexyl)phthalate (DEHP), or di(2-ethylhexyl)adipate (DEHA) at carcinogenic doses for 1 week. A close correlation between relative liver weights and hepatocarcinogenicity was observed (r = 0.910). (2) Administration of perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), simfibrate, or DL-040, for which hepatocarcinogenicity is not known, resulted in hepatomegaly in all treated groups, this being especially marked in the PFOA case. Therefore, PFOA may have strong hepatocarcinogenic potential. (3) Administration of the antioxidants butylated hydroxyanisole (BHA) or vitamin E (VE) did not affect the hepatomegaly induced by DEHP. These results suggest that the hepatomegaly may be an early biomarker for prediction of the potential hepatocarcinogenicity of peroxisome proliferators. However, this requires further clarification in terms of its relation to the oxidative stress thought to be involved in peroxisome proliferator-induced hepatocarcinogenesis.
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PMID:Hepatomegaly is an early biomarker for hepatocarcinogenesis induced by peroxisome proliferators. 162 84

In order to identify non-invasive, biochemical indicators of di(2-ethylhexyl)phthalate (DEHP) exposure, we have compared the effects in blood serum with biochemical effects in liver in rats fed a diet containing 0, 0.25, 0.75 and 2% DEHP for 2 weeks. After 3 days of treatment serum arylesterase activity levels and serum triglycerides were decreased to 60% and 20% of control values, respectively. After a 2-week treatment with DEHP the effects were generally stronger. Compared to a control group, serum arylesterase activity levels, serum triglycerides and serum cholesterol were decreased to 40%, 20% and 50%, respectively. Serum cholinesterase activity levels and serum albumin concentrations were increased by the DEHP treatment to 290% and 135% of control values, respectively. In the livers a hepatomegaly, an induction of cytochrome P-450 IVA1 and induction of the activity of palmitoyl-CoA oxidase and carnitine acetyl-CoA transferase was found to be 180%, 1080%, 1300% and 1700% of control values, respectively. The liver is a more sensitive target for DEHP exposure compared to the biochemical effects in serum, but determination of the serum parameters can be used to determine early biological effects of exposure to DEHP.
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PMID:Effect of di(2-ethylhexyl)phthalate on enzyme activity levels in liver and serum of rats. 227 65

The administration of 1.5 g/kg of di-(2-ethylhexyl)phthalate (DEHP), 50 or 10 micrograms/kg of luteinizing hormone-releasing hormone (LRH) to male Crj:Wistar rats for 1 week did not affect their testicular and prostatic gland weights. Co-administration of DEHP and LRH, however, induced testicular atrophy coincident with decreases in zinc and sulfhydryl concentration in the testis and reduction of the activity of testicular specific lactate dehydrogenase isozyme. These changes were similar to the results of high-dose administration of DEHP alone. Liver enlargement and hypolipidemia (reduction of serum cholesterol, triglycerides and phospholipids) occurred sometimes after co-administration of DEHP and LRH.
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PMID:Enhancing effects of luteinizing hormone-releasing hormone on testicular damage induced by di-(2-ethylhexyl)phthalate in rats. 274 71

The effects of various compounds known to be hepatic tumor promoters and toxins in the male B6C3F1 mouse liver, including di(2-ethylhexyl)phthalate (DEHP), acetaminophen (ACT), barbital (BB), and phenobarbital (PB) on hepatic metallothionein (MT) concentrations were assessed after chronic exposure. From 6 weeks of age, male mice were maintained on diets containing DEHP at 12,000 or 6000 ppm, ACT at 10,000 or 5000 ppm, BB at 1,000 ppm, or drinking water with PB at 500 ppm for up to 24 weeks. MT was measured in hepatic cytosol at 0, 2, 8, and 24 weeks of exposure. DEHP proved a very effective inducer, producing elevations of MT as high as 11-fold. The increases in hepatic MT with DEHP were both dose- and time-related. ACT was likewise effective in producing hepatic MT elevations (maximum 6.7-fold) in a dose- and time-related fashion. BB and PB, however, had no effect on hepatic MT levels at any time point. While DEHP, BB, and PB treatments produced hepatomegaly, histopathological analysis at 24 weeks revealed that in both DEHP- and ACT-treated livers hepatocellular proliferation was prominent while livers exposed to BB or PB showed predominantly hepatocellular hypertrophy. Gel-filtration of DEHP-treated liver cytosol revealed that zinc was associated with the MT peak. This peak also bound cadmium in vitro and could be extracted by heat treatment and selective acetone precipitation, both typical characteristics of MT. Further confirmation of the presence of MT after DEHP treatment was obtained by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (10 to 20% acrylamide). Results indicate that some, but not all, tumor promoters can induce target organ MT and that such an induction appears associated with those promoters inducing persistent cellular hyperplasia but not those inducing cellular hypertrophy.
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PMID:Induction of hepatic metallothionein in male B6C3F1 mice exposed to hepatic tumor promoters: effects of phenobarbital, acetaminophen, sodium barbital, and di(2-ethylhexyl) phthalate. 278 55

Di-n-octyl phthalate (DOP) is the straight chain isomer of di(2-ethylhexyl) phthalate (DEHP) which is a widely used plasticizer and an environmental contaminant. DEHP is a strong inducer of peroxisome proliferation in rat liver. This is significant since other compounds which are strong inducers of peroxisome proliferation have been reported to be weak carcinogens (Reddy, J.K. and Lalwani, N.D., CRC Crit. Rev. Toxicol., 12 (1983) 1). In contrast to DEHP, DOP causes little or no induction of liver peroxisomes (Mann, A.H. et al., Toxicol. Appl. Pharmacol., 77 (1985) 116, and Gray, T.J.B. et al., Toxicology, 28 (1983) 167). In the current study the ability of 1% DOP to promote the development of putative preneoplastic lesions was evaluated. The effect of feeding 0.5% DEHP as well as equimolar amounts of its 2 major metabolites, mono(2-ethylhexyl)phthalate (MEHP) and 2-ethylhexanol (2-EH) were also investigated. GGT+ foci were initiated in the livers of Sprague--Dawley male rats with a single dose of diethylnitrosamine (DEN) following partial hepatectomy. The control group of rats was fed a semipurified diet (Co) for 10 weeks while the experimental groups received the semipurified diet containing the respective compounds. Induction of peroxisome proliferation was monitored by carnitine acetyltransferase (CAT) levels. DOP treatment resulted in a 6-fold increase in the number of GGT+ foci (20.8 +/- 4.0 vs. 3.5 +/- 1.3; P less than 0.05). This was accompanied by no change in liver weight and only a slight increase in CAT activity when compared with control animals. In contrast to DOP, 2-EH produced essentially no effect with regard to number of foci, peroxisome proliferation or liver weight. DEHP and MEHP induced significant peroxisome proliferation and hepatomegaly but the number of foci were significantly lower than in 2-EH-treated rats. The mechanism for the promoting ability of DOP is not clear but would not appear to be related to peroxisome proliferation. Because of the close similarity of chemical structure and metabolism between DOP and DEHP, it is possible that studies to define the mechanism of DOP induced promotion might also serve to further clarify the mechanism of DEHP induced carcinogenesis.
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PMID:Di-n-octyl phthalate (DOP), a relatively ineffective peroxisome inducing straight chain isomer of the environmental contaminant di(2-ethylhexyl)phthalate (DEHP), enhances the development of putative preneoplastic lesions in rat liver. 287 11

The effect of prolonged dietary administration of the peroxisome proliferating plasticizer di(2-ethylhexyl)phthalate (DEHP) was studied on liver carcinogenesis initiated by N-2-fluorenylacetamide (FAA) and compared with that of the neoplasm-promoter phenobarbital (PB). Also, DEHP was studied as an initiator by giving it in place of FAA before PB. Male rats were fed FAA for 7 weeks to induce hepatocellular altered foci, and were subsequently given no chemical, 12,000 p.p.m. DEHP or 500 p.p.m. PB for 24 weeks in the diet. In the rats fed DEHP, substantial hepatomegaly and peroxisome proliferation were induced. No evidence of induction of hepatocellular altered foci or hepatic neoplasms was found either when DEHP was given alone for 24 weeks or for 7 weeks followed by PB. Also, DEHP fed for 24 weeks had no promoting effect on liver altered foci that were induced by FAA and produced little or no enhancement of the occurrence of FAA-induced liver neoplasms. In contrast, PB exerted a marked enhancing effect on foci and substantially increased the incidence and multiplicity of liver neoplasms. Thus, the findings demonstrate that DEHP did not have either a rapid initiating activity, a significant sequential syncarcinogenic activity, or a promoting effect on liver carcinogenesis under conditions in which numerous agents with such activities have been identified.
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PMID:Lack of rapid initiating, promoting or sequential syncarcinogenic effects of di(2-ethylhexyl)phthalate in rat liver carcinogenesis. 359 21

Effects of di-(2-ethylhexyl)adipate (DOA) and di-(2-ethylhexyl)phthalate (DEHP), plasticizers for polyvinylchloride products, on concentrations and compositions of hepatic phospholipids were studied in rats. When administered to rats at a 2% level for 2 wk, both DOA and DEHP caused a hepatomegaly, an increase in hepatic phospholipids and a decrease an increase in hepatic phospholipids and a decrease in the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE). In the comparable study with mice, the alkyl moiety of DOA was found to be responsible for these alterations. DOA and DEHP specifically altered fatty acid compositions of PC and PE: there was an increase in oleic and palmitic acids and a decrease in stearic and docosahexaenoic acids in PC and an increase in arachidonic acid at the expense of docosahexaenoic acid in PE. In addition, DOA caused an increase in the trienoic and tetraenoic molecular species in PC and an increase in the 1-palmitoyl-2-arachidonyl (16:0@20:4) species in PE. Thus, the effects of DOA on the lipid dynamics resembled those observed with DEHP, although the magnitude was slightly moderated.
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PMID:Alteration of hepatic phospholipids in rats and mice by feeding di-(2-ethylhexyl)adipate and di-(2-ethylhexyl)phthalate. 365 95

Female F-344 rats were fed a diet containing up to 1.2% di(2-ethylhexyl)phthalate (DEHP) for 2 years, which previously resulted in hepatocarcinogenesis under bioassay conditions. Peroxisome proliferation, decreased glutathione peroxidase activity, and lipofuscin accumulation were all associated with prolonged feeding of 1.2% DEHP and induction of hepatic neoplasia. These results establish a potential role for persistent peroxisome proliferation and oxidative injury in the hepatocarcinogenicity of dietary DEHP. Increased hepatocellular proliferation and hepatomegaly were not detected. DEHP feeding did not increase the volume density of basophilic or ATPase-deficient foci of altered hepatocytes, suggesting that these lesions are not suitable indicators of DEHP carcinogenesis.
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PMID:Association of persistent peroxisome proliferation and oxidative injury with hepatocarcinogenicity in female F-344 rats fed di(2-ethylhexyl)phthalate for 2 years. 369 May 5


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