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)

The dose-response for key hepatic effects of the peroxisome proliferator ciprofibrate, 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2- methylpropanoic acid, was delineated in mice and strain differences in response were demonstrated. Ciprofibrate was fed at concentrations ranging from 0.1 to 250 ppm to male C57BL/6N and BALB/c mice and the induction of hepatic acyl-CoA oxidase and catalase, peroxisomal enzymes involved in the formation and degradation of hydrogen peroxide, and liver hepatomegaly and mitogenesis were measured. No effect was found for enzyme induction at 5.0 ppm or less in either strain. Likewise, hepatomegaly was not found at 5.0 ppm, but mitogenesis was observed in BALB/c mice at 1.0 ppm. C57BL/6N mice demonstrated greater basal and postexposure acyl-CoA oxidase activity than BALB/c mice, while BALB/c mice demonstrated greater catalase activity and induction of liver mitogenesis. The threshold exposure level for induction of acyl-CoA oxidase activity was approximately the same as that for induction of mitogenesis in C57BL/6N mice; in contrast, the threshold exposure level for induction of acyl-CoA oxidase activity was at least one order of magnitude greater than that required for induction of mitogenesis in BALB/c mice. Thus, the induction of the peroxisomal enzyme involved in the formation of hydrogen peroxide and increased mitogenesis are not mechanistically linked. The differential effects observed in the two mouse strains provide the basis for development of a quantitative model of peroxisome proliferator-induced carcinogenicity in which cellular effects can be related to carcinogenicity.
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PMID:Dose-response relationships of hepatic acyl-CoA oxidase and catalase activity and liver mitogenesis induced by the peroxisome proliferator ciprofibrate in C57BL/6N and BALB/c mice. 156 28

Lantadene A (22 beta-angeloyloxy-3-oxo-olean-12-en-28-oic acid), a pentacyclic triterpenoid compound from lantana (Lantana camara) leaves has been obtained in two polymorphic forms I and II. Form I had white, fluffy, and rod-shaped uniform crystals. Form II particles were irregular, shining, and polyhedral. The two forms differed in melting behavior. The powder x-ray diffraction of form I showed sharp peaks whereas from II did not contain distinct peaks. From single-crystal three-dimensional x-ray structure determination, the molecular structure of form I has been established. A/B and B/C rings of the molecule are trans fused while D/E rings are cis fused. The packing of the molecule is stabilized by hydrogen bonding. Form I of lantadene A was non-toxic to guinea pigs on oral administration. Form II induced ictericity and toxicity associated with decrease in feed intake and fecal output, hepatomegaly, increase in plasma bilirubin, and acid phosphatase activity.
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PMID:Molecular structure, polymorphism, and toxicity of lantadene A, the pentacyclic triterpenoid from the hepatotoxic plant Lantana camara. 188 Jul 89

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

An increasing number of beneficial and economically important drugs, industrial chemicals, and agrichemicals are being found to cause a dose-related hepatomegaly in rodent species which is associated with the proliferation of the subcellular organelle, the peroxisome. The prolonged proliferation of hepatocellular peroxisomes and the enhanced production of the normal peroxisomal metabolic byproduct, hydrogen peroxide, in these animals during chronic bioassays has been hypothesized to account for the tumorigenicity of several of these compounds, most of which lack any measurable genotoxicity in in vitro and in vivo assays. This paper briefly reviews the basic morphology and enzymology of the peroxisome and its relationship to specific pathologic changes in animals. The potential impact of the mechanism of action of peroxisome proliferators upon the design of toxicity studies and, in conjunction with interspecies sensitivity data, upon risk assessment is discussed.
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PMID:Chemically induced proliferation of peroxisomes: implications for risk assessment. 305 Nov 40

Cancer cachexia contributes to the demise of a significant number of cancer patients, and severe loss of adipose tissue is a prominent component of this syndrome. One of the products of fat catabolism is glycerol, and its turnover is elevated in the cancerous state. Since glycerol is also one of the most important gluconeogenic substrates, its role in the augmented and abnormal gluconeogenesis of cancer hosts needs to be defined. In the present study, we examined hepatic glycerol metabolism in livers of Fischer 344 rats bearing s.c. nonmetastatic adenocarcinoma R3230AC. Five weeks after tumor inoculation, the liver was removed and perfused with 5 mM [2-13C]glycerol while 13C nuclear magnetic resonance spectroscopy was performed. In the livers of tumorous rats, we found: (a) lipogenesis from glycerol was augmented; (b) the rate of hepatic glycerol uptake was unchanged; (c) glucose production from glycerol was not altered; and (d) conversion of glycerol 3-phosphate to dihydroxyacetone phosphate remains the rate-limiting step. Therefore, it appears that, in cancer hosts, diminished glycerol clearance is not due to reduction in hepatic glycerol uptake or metabolism, and the abnormal gluconeogenesis involves the pathway prior to the entry of glycerol. The exaggerated lipolysis is probably used for the pathological hepatomegaly, and the availability of the cytosolic hydrogen acceptor remains the rate-limiting factor for glycerol metabolism.
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PMID:Hepatic glycerol metabolism in tumorous rats: a 13C nuclear magnetic resonance study. 785 Jul 86

The purpose of the workshop "Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?" was to provide a review of the current state of the science on the relationship between peroxisome proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce liver tumors in rats and mice and whether these events occur in humans. A primary goal of the workshop was to determine where consensus might be reached regarding the interpretation of these data relative to the assessment of potential human risks. A core set of biochemical and cellular events has been identified in the rodent strains that are susceptible to the hepatocarcinogenic effects of peroxisome proliferators, including peroxisome proliferation, increases in fatty acyl-CoA oxidase levels, microsomal fatty acid oxidation, excess production of hydrogen peroxide, increases in rates of cell proliferation, and expression and activation of the alpha subtype of the peroxisome proliferator-activated receptor (PPAR-alpha). Such effects have not been identified clinically in liver biopsies from humans exposed to peroxisome proliferators or in in vitro studies with human hepatocytes, although PPAR-alpha is expressed at a very low level in human liver. Consensus was reached regarding the significant intermediary roles of cell proliferation and PPAR-alpha receptor expression and activation in tumor formation. Information considered necessary for characterizing a compound as a peroxisome proliferating hepatocarcinogen include hepatomegaly, enhanced cell proliferation, and an increase in hepatic acyl-CoA oxidase and/or palmitoyl-CoA oxidation levels. Given the lack of genotoxic potential of most peroxisome proliferating agents, and since humans appear likely to be refractive or insensitive to the tumorigenic response, risk assessments based on tumor data may not be appropriate. However, nontumor data on intermediate endpoints would provide appropriate toxicological endpoints to determine a point of departure such as the LED10 or NOAEL which would be the basis for a margin-of-exposure (MOE) risk assessment approach. Pertinent factors to be considered in the MOE evaluation would include the slope of the dose-response curve at the point of departure, the background exposure levels, and variability in the human response. Copyright 1998 Academic Press.
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PMID:Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? 961 23

The purpose of the workshop "Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?" was to provide a review of the current state of the science on the relationship between peroxisome proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce liver tumors in rats and mice and whether these events occur in humans. A primary goal of the workshop was to determine where consensus might be reached regarding the interpretation of these data relative to the assessment of potential human risks. A core set of biochemical and cellular events has been identified in the rodent strains that are susceptible to the hepatocarcinogenic effects of peroxisome proliferators, including peroxisome proliferation, increases in fatty acyl-CoA oxidase levels, microsomal fatty acid oxidation, excess production of hydrogen peroxide, increases in rates of cell proliferation, and expression and activation of the alpha subtype of the peroxisome proliferator-activated receptor (PPAR-alpha). Such effects have not been identified clinically in liver biopsies from humans exposed to peroxisome proliferators or in in vitro studies with human hepatocytes, although PPAR-alpha is expressed at a very low level in human liver. Consensus was reached regarding the significant intermediary roles of cell proliferation and PPAR-alpha receptor expression and activation in tumor formation. Information considered necessary for characterizing a compound as a peroxisome proliferating hepatocarcinogen include hepatomegaly, enhanced cell proliferation, and an increase in hepatic acyl-CoA oxidase and/or palmitoyl-CoA oxidation levels. Given the lack of genotoxic potential of most peroxisome proliferating agents, and since humans appear likely to be refractive or insensitive to the tumorigenic response, risk assessments based on tumor data may not be appropriate. However, nontumor data on intermediate endpoints would provide appropriate toxicological endpoints to determine a point of departure such as the LED10 or NOAEL which would be the basis for a margin-of-exposure (MOE) risk assessment approach. Pertinent factors to be considered in the MOE evaluation would include the slope of the dose-response curve at the point of departure, the background exposure levels, and variability in the human response.
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PMID:Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? 962 96

Peroxisomeproliferators (PPs) cause hepatomegaly, peroxisome proliferation, and hepatocarcinogenesis in rats and mice. Conversely, hamsters are less responsive to these compounds. PPs increase peroxisomal beta-oxidation and P4504A subfamily activity, which has been hypothesized to result in oxidative stress. We hypothesized that differential modulation of glutathione-related defenses could account for the resulting difference in species susceptibility following PP administration. Accordingly, we measured glutathione S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GR) activities, and total glutathione (GSH) in male Sprague-Dawley rats and Syrian hamsters fed two doses of three known peroxisome proliferators [dibutylphthalate (DBP), gemfibrozil, and Wy-14,643] for 6, 34, or 90 days. In rats, decreases in GR, GST, and selenium-dependent GPx were observed following PP treatment at various time points. In hamsters, we observed higher basal levels of activities for GR, GST, and selenium-dependent GPx compared to rats. In addition, hamsters showed decreases in GR and GST activities following PP treatment. Interestingly, selenium-dependent GPx activity was increased in hamsters following treatment with Wy-14,643 and DBP. Treatment for 90 days with Wy-14,643 resulted in no change in GPx1 mRNA in rats and increased GPx1 mRNA in hamsters. Sporadic changes in total GSH and selenium-independent GPx were observed in both species. This divergence in the hydrogen peroxide detoxification ability between rats and hamsters could be a contributing factor in the proposed oxidative stress mechanism of PPs observed in responsive and nonresponsive species.
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PMID:Effects of peroxisome proliferators on glutathione and glutathione-related enzymes in rats and hamsters. 1118 Nov 9

Peroxisome proliferators are nongenotoxic rodent carcinogens that act as tumor promoters by increasing cell proliferation; however, their precise mechanism of action is not well understood. Oxidative DNA damage caused by leakage of hydrogen peroxide (H2O2) from peroxisomes was hypothesized initially as the mechanism by which these compounds cause liver tumors. It seems unlikely that oxidants of peroxisomal origin explain the mechanism of action of peroxisome proliferators because treatment with these compounds in vivo does not lead to increased H2O2 production. On the other hand, Kupffer cell-derived oxidants, such as superoxide, may play a role in initiating tumor nerosis factor-alpha (TNF-alpha) production that leads to hepatocyte proliferation. Peroxisome proliferators have been shown to activate Kupffer cells both in vitro and in vivo, and the use of Kupffer cell inhibitors such as methyl palmitate and dietary glycine have demonstrated that Kupffer cells are responsible for hepatocyte proliferation by mechanisms involve TNF-alpha. Moreover, peroxisome proliferators activate the transcription factor NF-kappaB, one of the major regulators of TNF-alpha expression, in Kupffer cells. Importantly, activation of NF-kappaB by peroxisome proliferators was shown to be oxidant-dependent, leading to the hypothesis that oxidants of Kupffer cell origin are involved in the mechanism of action. Many of the effects of peroxisome proliferators, including peroxisome induction and hepatomegaly, involve the peroxisome proliferator-activated receptor-alpha (PPARalpha). Recently, it was shown that peroxisome proliferator-induced cell proliferation and tumors require the PPARalpha. However, PPARalpha is not involved in TNF-alpha production by Kupffer cells because it is not expressed in this cell type. How it is involved in liver tumor remains unclear and one possible explanation is that both Kupffer cell TNF-alpha and parenchymal cell PPARalpha are required. Collectively, recent data are consistent with the hypothesis that oxidants play a role in signaling hepatocellular proliferation due to peroxisome proliferators via activation of NF-kappaB and incrase in mitogenic cytokines such as TNF-alpha.
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PMID:Novel role of oxidants in the molecular mechanism of action of peroxisome proliferators. 1122 71

Toxicokinetic and mode of action data for DEHP reduce the concern for its potential carcinogenic hazard to human health. Chronic, high dose ingestion of DEHP and related peroxisome proliferators (PP) by mice and rats precipitate the following: activation of peroxisome proliferator activated receptor (PPARalpha) and its binding to peroxisome proliferator response elements (PPREs) within promoters of PP-responsive genes, peroxisome proliferation, increased microsomal fatty acid oxidation, increased hepatic hydrogen peroxide, hepatomegaly, hyperplasia and subsequent neoplasia. Neither peroxisome proliferation nor increased liver cancer occur in patients treated with pharmacologic doses of PP. Species differences in endogenous PPARalpha expression and differential activity of the peroxisome proliferator response element (PPRE) contribute to the failure of humans to respond in a manner qualitatively similar to that of rats or mice. Where it can be demonstrated that a mechanism for rodent tumor formation has no relevance for humans, then a substance which elicits a carcinogenic response in the test species via that mechanism should not be classified as anything other than an animal carcinogen. Systemic noncarcinogenic endpoints are available for definition of a DEHP reference dose. Considerable difficulty is encountered in the revision of promulgated regulations and in public risk communication when a material is no longer considered a carcinogenic hazard to humans.
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PMID:Weight-of-evidence versus strength-of-evidence in toxicologic hazard identification: Di(2-ethylhexyl)phthalate (DEHP). 1124 42


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