UMLS:C0019209 - FACTA Search

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Query: UMLS:C0019209 (hepatomegaly)
5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of BR-931, an ethanolamine derivative of Wy-14,643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinythio]acetic acid, at a dietary concentration of 0.125% for 3 weeks to male F-344 rats, resulted in a significant enlargement of the liver. The hepatomegaly appeared to be due to liver cell hyperplasia and hypertrophy resulting, in part, from peroxisome and smooth endoplasmic reticulum proliferation. The hepatic catalase and carnitine acetyltransferase activities increased significantly in association with peroxisome proliferation. The hepatomegaly and peroxisome proliferation induced by BR-931 were comparable in degree to those resulting from feeding of an equivalent dose of Wy-14,643. All these hepatic effects were reversible when the drugs were withdrawn from the diet. Screening of new compounds for hepatic peroxisome proliferation and for increases in peroxisome-associated enzymes may prove to be an adjunct to evaluating their potency as hypolipidemic agents, in view of frequent association between hepatic peroxisome proliferation and hypolipidemia.
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PMID:Hepatic peroxisome proliferation: induction by BR-931, a hypolipidemic analog of WY-14,643. 70 42

The comparative hypolipidemic and hepatic peroxisome proliferative activities of a series of thioacetic acid pyrimidines were evaluated in male mice. [4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643) produced significant hepatomegaly and peroxisome proliferation in liver cells. This compound also increased the hepatic catalase and carnitine acetyltransferase activities and lowered serum cholesterol and triglyceride levels. The structurally related analogs, Wy-15,690, Wy-15,672, Wy-15,746 and Wy-15,496, which lacked hypolipidemic effect failed to induce hepatomegaly and peroxisome proliferation. No substantial increase in catalase and carnitine acetyltransferase activities was noted. It is concluded that the hepatic peroxisome proliferative effect is closely related to the hypolipidemic activity, rather than to any specific chemical structure.
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PMID:Hepatic effects of some [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (WY-14,643) analogs in the mouse. 85 95

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

The dose and time dependency of peroxisome proliferation and hepatocyte replication was evaluated in the liver of rats fed the peroxisome proliferator and hepatocarcinogen, Wy-14,643. Male F344 rats were fed NIH07 diet blended with Wy-14,643 at 0, 5, 10, 50, 100, or 1000 ppm for 1, 3, 6, or 13 weeks. Hepatomegaly was induced by Wy-14,643 at all doses and at all time points. Peroxisome proliferation was present in rats fed 5 ppm Wy-14,643 as early as 1 week, as determined by the peroxisome-specific NAD+ reduction of palmitoyl CoA (PCO) and the peroxisome-associated activity of carnitine acetyltransferase (CAT) (5- and 11-fold over control, respectively). The elevations of PCO and CAT were dose-dependent from 5 to 50 ppm and then plateaued from 50 to 1000 ppm throughout the treatment period. Hepatocellular replication, evaluated by nuclear histoautoradiography ([3H]thymidine labeling, 6-day infusion), was increased in all Wy-14,643 dose groups after 1 week of treatment (5 ppm, 4-fold; 10 ppm, 5-fold; 50 ppm, 13-fold; 100 ppm, 12-fold; and 1000 ppm, 13-fold over controls). However, in 5 and 10 ppm groups this cell replication returned to control levels by 3 weeks. In contrast, 50, 100, and 1000 ppm groups had sustained increases in cell replication up to 13 weeks (13 weeks: 6-, 7-, and 9-fold over controls, respectively). We have demonstrated that Wy-14,643 can induce peroxisome proliferation at 5 ppm, a dose 200 times lower than the dose shown to be highly hepatocarcinogenic in rats (100% incidence by 60 weeks).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dose-related effects of the hepatocarcinogen, Wy-14,643, on peroxisomes and cell replication. 160 Dec 4

Chronic ciprofibrate administration resulted in distinct differences in hepatic responses between the two species examined. In the rat, hepatomegaly was observed with the coordinate induction of carnitine acetyltransferase, peroxisomal beta-oxidation and cytochrome P450IVA1 activities. The latter induction of cytochrome P450IVA1-dependent fatty acid hydroxylase activity was specific to this cytochrome P450 sub family, as ciprofibrate pretreatment resulted in an inhibition of the enzyme activities associated with the cytochrome P450 IIB and IA sub-families. Induction of mitochondrial enzymes were also noted in the rat, but at a substantially lower level than the microsomal and peroxisomal enzyme changes noted above. The majority of these enzyme changes were reversible in the rat after a 4-week, inducer-free period. In contrast, the marmoset displayed a different pattern of enzyme changes in response to ciprofibrate and at the high dose level, inhibition of microsomal fatty acid hydroxylase activity was observed in addition to no change in carnitine acetyltransferase activity. Although peroxisomal beta-oxidation activity was induced in the marmoset, the specific activity was 10-fold lower than in the rat, concomitant with only minimum changes in the liver: body weight ratio. Taken collectively, our data have demonstrated that the marmoset is relatively refractory to ciprofibrate-induced liver enzyme changes with the implication that the extrapolation of the associated hepatotoxicity clearly documented in rodents must be viewed with extreme caution in non-human primates.
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PMID:Comparative induction of cytochrome P450IVA1 and peroxisome proliferation by ciprofibrate in the rat and marmoset. 190 30

The influence of ciprofibrate, a potent oxyisobutyrate derivative, on several hepatic enzyme parameters was studied in five rat strains following a 14-day treatment period. Ciprofibrate-dependent hepatomegaly was observed at two dose levels (2 and 20 mg/kg) in all rat strains examined. A 10- to 15-fold induction in the 12-hydroxylation of lauric acid with a less marked 1.5- to 5-fold induction of 11-hydroxylation was observed in treated animals. This dose-dependent increase in fatty acid hydroxylase activity was associated with a maximal 10-fold increase in the specific content of cytochrome P-450 IVA1 isoenzyme apoprotein, as assessed immunochemically using an ELISA technique. The activities of the cytochrome P-450 I (IA1 and IA2) and II (IIB1 and IIB2) families, as measured by ethoxyresorufin-O-deethylase and benzphetamine-N-demethylase activities respectively, were decreased on treatment. In the mitochondria, monoamine oxidase activity was significantly decreased at the higher dose level whereas alpha-glycerophosphate dehydrogenase activity was elevated. Total carnitine acetyltransferase activity (mitochondrial and peroxisomal) and peroxisomal beta-oxidation were markedly increased at both dose levels in all strains examined. Cytosolic glutathione peroxidase activity, measured using both t-butylhydroperoxide and hydrogen peroxide as substrates, was decreased on treatment to approximately 50% of the control value. In treated animals, a marked increase in mRNA levels coding for cytochrome P-450 IVA1 and the peroxisomal bifunctional protein of the fatty acid beta-oxidation spiral was observed. However, mRNA levels coding for glutathione peroxidase appeared unchanged following ciprofibrate administration, in contrast to the above-noted decrease of glutathione peroxidase enzyme activity. Taken collectively, our results have further substantiated a close association between the induction of microsomal cytochrome P-450 IVA1, peroxisomal beta-oxidation and total carnitine acetyltransferase activity in rat liver, and have performed a conceptual basis for the rationalization of the chronic toxicity of peroxisome proliferators in this species.
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PMID:Characterization of the hepatic responses to the short-term administration of ciprofibrate in several rat strain. Co-induction of microsomal cytochrome P-450 IVA1 and peroxisome proliferation. 239 Jan 5

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 effects of bezafibrate on hepatic peroxisome-associated enzymes of rats, mice, guinea pigs, hamsters, rabbits, dogs and monkeys were examined. Dogs and monkeys were given bezafibrate orally at 30 mg/kg body wt daily for 2 weeks and at 125 mg/kg body wt daily for 13 weeks, respectively, and other species at 100 mg/kg daily for 2 weeks. In male rats, marked changes were observed in the activities of catalase (1.73-fold), D-amino acid oxidase (DAAO; 0.56-fold), fatty acyl-CoA oxidizing system (FAOS; 12.9-fold) and carnitine acetyltransferase (CAT; 35.8-fold); in female rats, the changes were less than in the males. In mice, there were no apparent sex differences in the responses of hepatic peroxisomal enzymes to bezafibrate and the increases in the activities of catalase, FAOS and CAT were 1.76-, 3.75- and 7.94-fold respectively. In guinea pigs, only slight increases in the activities of FAOS (3.00-fold) and CAT (2.83-fold) were observed. In hamsters, the increases in catalase, FAOS and CAT activities, were 1.23-, 2.19- and 2.77-fold respectively. Although rabbits and dogs showed slight increases in CAT activity, no significant response to the drug was observed in monkeys. Hepatomegaly and the increase of hepatic content of peroxisome proliferation-associated polypeptide (PPA-80), which has been recognized as a peroxisomal bifunctional protein in the fatty acid beta-oxidation pathway, were observed only in rats and mice. These results show that there were marked species differences in the effects of bezafibrate on hepatic peroxisomes, and that bezafibrate induced hepatic peroxisome proliferation in rodents, especially rats and mice.
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PMID:Species differences in the effects of bezafibrate, a hypolipidemic agent, on hepatic peroxisome-associated enzymes. 291 22

Ammonium perfluorooctanoate (APFO) is known to induce a striking hepatomegaly in rats. The purpose of these studies was to determine the causes of the hepatomegaly and compare the effect to other liver-enlarging compounds. Since the total hepatic DNA content was similar in control and APFO-treated rats, the hepatomegaly represented a hypertrophic rather than a hyperplastic response. The cytochrome P-450 content and activity of benzphetamine N-demethylase increased in the livers of APFO-treated rats, indicating the proliferation of the smooth endoplasmic reticulum. In contrast to the membrane-bound enzymes, the soluble enzymes glutathione S-transferase and UDPglucuronyltransferase were unaffected by APFO treatment. The activity of carnitine acetyltransferase was disproportionately increased relative to carnitine palmitoyltransferase in the livers of APFO vs that in control rats, confirming the predominant proliferation of peroxisomes vs that of mitochondria. Morphological studies confirmed the proliferation of the endoplasmic reticulum, mitochondria, and peroxisomes in the livers of APFO-treated rats. In contrast to many other peroxisome proliferating agents, APFO did not possess hypolipidemic activity.
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PMID:Biochemical and morphological studies of ammonium perfluorooctanoate-induced hepatomegaly and peroxisome proliferation. 360 46

The effect of some hypolipidemic agents, which are commercially available and those being developed, on certain biochemical values and on hepatic peroxisomal enzyme activities of rats were examined. Clofibrate (0.25% (w/w) in the diet), p-chlorophenoxy-isobutyryl-glycinamide (CGA) (0.25%), clinofibrate (0.1%), KCD-232 (0.1%) and MLM-160 (0.1%) increased the activities of peroxisomal fatty acyl-CoA oxidizing system, carnitine acetyltransferase, and mitochondrial carnitine palmitoyltransferase. Of peroxisomal enzymes, catalase activity was increased by the above agents, whereas the activities of D-amino acid oxidase and urate oxidase were decreased by clofibrate and CGA, and but were increased by KCD-232 and MLM-160 which are structurally unrelated to clofibrate. No influence on these enzyme activities by AL-369 and probucol treatments were observed. Hepatomegaly was induced by clofibrate, CGA, KCD-232 and MLM-160. Concerning serum lipid levels, clofibrate, CGA, clinofibrate, KCD-232 and MLM-160 decreased both cholesterol and triglyceride levels, whereas probucol decreased only cholesterol level. AL-369 had no influence on serum lipid levels under this condition using normolipemic rat. From these results, it was concluded that differing clofibrate and CGA, clinofibrate, MLM-160 and KCD-232 might not induce peroxisome proliferation in hepatic cells, although these have an influence on the enzyme composition of hepatic peroxisomes.
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PMID:Effects of some hypolipidemic agents on biochemical values and hepatic peroxisomal enzymes in rats: comparison of probucol, CGA, KCD-232, MLM-160, AL-369 and clinofibrate with clofibrate. 362 48

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