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 plasticizer di(2-ethylhexyl) phthalate (DEHP), to which humans are extensively exposed, was found to be hepatocarcinogenic in rats and mice. DEHP is potentially set free from objects made of synthetic materials (e.g., those used in medicine). Chronically, the greatest amounts are transferred to persons undergoing hemodialysis (up to 3.1 mg/kg b.w. per day) who would thus be considered the individuals most endangered by tumorigenesis. Although toxicokinetics seem to play a certain unclear role in the course of DEHP-related toxicity, toxicodynamic factors appear more decisive. DEHP is a representative of "peroxisome proliferators" (PP), a distinct group of substances that, in rodents, do not only induce peroxisomes but also specific enzymes in other organelles, organ growth, and DNA synthesis. The cluster of the characteristic effects of PP is generally, although perhaps not quite appropriately summarized as "peroxisome proliferation," and is strongest in the liver. The lowest observed effect level (LOEL) and the no observed effect level (NOEL) of peroxisome proliferation in the rat, as determined by the induction of specific enzymes (peroxisomal beta-oxidation, carnitine-acetyl-transferase, cytochrome P-452), DNA synthesis, and hepatomegaly, may be assumed as 50 and 25 mg/kg b.w. per day, respectively. DEHP and other carcinogenic PP are neither genotoxic nor tumor initiators, but they appear to be tumor promoters, also implicating a threshold level for the carcinogenic effect. Although a causal relationship between a particular effect of peroxisome proliferation and hepatocarcinogenesis is as yet unknown, peroxisome proliferation as a whole phenomenon appears to be associated with the potential of tumor induction, as shown by comparison of the relative strength of individual PP and by comparison of species and organ specificities. Likewise, LOEL and NOEL of rodent carcinogenesis, that is, 300 and 50 to 100 mg/kg b.w. per day, respectively, are above but not too far from the corresponding values for the investigated parameters of peroxisome proliferation. Thus, with respect to dose alone, worst-case exposure in hemodialysis patients is at least 16-fold below the LOEL of any characterized PP-specific effect of DEHP and approximately 100-fold below that of DEHP-related tumorigenesis. Also, primates are less responsive to PP than rats with respect to the investigated biochemical and morphological parameters. If this lower primate responsiveness is extrapolated to estimate carcinogenicity in humans, we might thus arrive at an even larger safety margin than when based on exposure alone. Doses of PP hypolipidemics that had clearly induced several indicators of peroxisome proliferation in rats did not cause any clear-cut enhancements in the peroxisomes of patients, even though most of these hypolipidemics were considerably stronger PP than DEHP. Thus, an actual threat to humans by DEHP seems rather unlikely. Accordingly, hepatocarcinogenesis was neither enhanced in workers exposed to DEHP nor in patients treated with hypolipidemics.
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PMID:Hepatocarcinogenic potential of di(2-ethylhexyl)phthalate in rodents and its implications on human risk. 881 83

Male and female CD rats were administered one of two dose levels of clofibrate, gemfibrozil, or bezafibrate daily by oral gavage for a period of 14 days in order to establish an empirical data base using the Charles River CD rat with a single class of drugs against which the potency of novel proprietary compounds could be compared. Subsequent gross examination of the liver indicated significant and dose-related increases in relative and absolute liver weights in males following clofibrate and gemfibrozil. In females, absolute and relative liver weights were significantly elevated to a similar degree with either dose of gemfibrozil, and absolute liver weights were higher in clofibrate-dosed animals. Bezafibrate had no effect on female liver weights. Clofibrate and gemfibrozil increased hepatic palmitoyl CoA beta-oxidation in both sexes; however, clofibrate had the greater effect in males and gemfibrozil had the least effect in females. Bezafibrate treatment resulted in a very pronounced elevation of palmitoyl CoA beta-oxidation in the males but had no similar effect in the females. Concurrent ELISA analysis for cytochrome CYP4A revealed very good correspondence between beta-oxidation and cytochrome induction for each of the three compounds in males, but other cytochromes were not greatly affected, except CYP1A1 which was elevated in bezafibrate-dosed females. For males, further analysis for markers of cellular proliferation, namely cyclin-dependent kinases (CDK) and proliferating cell nuclear antigen (PCNA), indicated dose-related increases for both with clofibrate, increases at the high dose for gemfibrozil, and, for PCNA, a dose-related increase for bezafibrate. In females, both markers for cell proliferation showed either slight or no increases following any of the three drug treatments. These results demonstrate clear sex-dependent differences in terms of relative potency in the hepatic response of the Sprague-Dawley-derived rat to these peroxisome proliferators. Bezafibrate is most potent and gemfibrozil is least potent in stimulating peroxisome-associated beta-oxidation and cytochrome P450 4A induction in the males. Even though gemfibrozil significantly increased liver weights, beta-oxidation and cytochrome P450 4A in the females increased only after clofibrate treatment, although to a lesser degree than in the males administered the same dose. Similar sex-related differences were observed for cell proliferation. In conclusion, sex-related differences were noted in the potency to stimulate acyl Co-A oxidation, its association with hepatomegaly, and the stimulation of cell proliferation, but CYP4A induction always accompanied any substantial drug-dependent increases in beta-oxidation.
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PMID:Hepatic microsomal enzyme induction, beta-oxidation, and cell proliferation following administration of clofibrate, gemfibrozil, or bezafibrate in the CD rat. 900 43

Compounds that cause peroxisome proliferation in rats and mice have been reported to interfere with mitochondrial (mt) bioenergetics and possibly biogenesis. The purpose of this investigation was to establish whether proliferation of peroxisomes and mitochondria are necessarily related. Perfluorooctanesulfonate (PFOS) and N-ethyl perfluorooctanesulfonamido ethanol (N-EtFOSE) were investigated as peroxisome proliferators in comparison to perfluorooctanoic acid (PFOA). Three parameters were chosen to assess peroxisome proliferation, stimulation of lauroyl CoA oxidase activity, reduction of serum cholesterol concentration, and hepatomegaly. mt Biogenesis was assessed through cytochrome oxidase activity, cytochrome content and mitochondrial DNA (mtDNA) copy number. PFOA, PFOS, or N-EtFOSE was administered via a single i.p. injection at 100 mg/kg in male rats, and measurements were made 3 days later. In this model, PFOS and PFOA share similar potencies as peroxisome proliferators, whereas N-EtFOSE showed no activity. mt Endpoints were altered only in the PFOA treatment group, which consisted of a decrease cytochrome oxidase activity in liver tissue and an increase in the mtDNA copy number. None of the perfluorooctanoates significantly altered mt cytochrome content following acute in vivo treatment. These data demonstrate that acute administration of PFOS or PFOA causes hepatic peroxisome proliferation in rats. However, stimulation of mt biogenesis is not a characteristic response of all peroxisome proliferators.
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PMID:Perfluorooctanoate, perflourooctanesulfonate, and N-ethyl perfluorooctanesulfonamido ethanol; peroxisome proliferation and mitochondrial biogenesis. 1187 71

A boy presented with lactic acidosis, hepatomegaly, hypoglycemia, generalised icterus, and muscle hypotonia in the first weeks of life. At the age of 2 months, neonatal giant cell hepatitis was diagnosed by light microscopy. Electron microscopy of the liver revealed an accumulation of abnormal mitochondria and steatosis. Skeletal muscle was normal on both light and electron microscopy. At the age of 5 months, the patient died of liver failure. Biochemical studies of the respiratory chain enzymes in muscle showed that cytochrome-c oxidase (complex IV) and succinate-cytochrome-c oxidoreductase (complex II + III) activities were (just) below the control range. When related to citrate synthase activity, however, complex IV and complex II + III activities were normal. Complex I activity was within the control range. The content of mitochondrial DNA (mtDNA) was severely reduced in the liver (17% to 18% of control values). Ultracytochemistry and immunocytochemistry of cytochrome-c oxidase demonstrated a mosaic pattern of normal and defective liver cells. In defective cells, a reduced amount of the mtDNA-encoded subunits II-III and the nuclear DNA-encoded subunits Vab was found. Cells of the biliary system were spared. Immunohistochemistry of mtDNA replication factors revealed normal expression of DNA polymerase gamma. The mitochondrial single-stranded binding protein (mtSSB) was absent in some abnormal hepatocytes, whereas the mitochondrial transcription factor A (mtTFA) was deficient in all abnormal hepatocytes. In conclusion, depletion of mtDNA may present as giant cell hepatitis. mtTFA and to a lesser degree mtSSB are reduced in mtDNA depletion of the liver and may, therefore, be of pathogenetic importance. The primary defect, however, is still unknown.
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PMID:Depletion of mitochondrial DNA in the liver of an infant with neonatal giant cell hepatitis. 1195 53

Conazoles are environmental and pharmaceutical fungicides. The present study relates the toxicological effects of conazoles to alterations of gene and pathway transcription and identifies potential modes of tumorigenic action. In a companion study employing conventional toxicological bioassays (Allen et al., 2006), male CD-1 mice were fed triadimefon, propiconazole, or myclobutanil in a continuous oral-dose regimen for 4, 30, or 90 days. These conazoles were found to induce hepatomegaly, to induce high levels of hepatic pentoxyresorufin-O-dealkylase activity, to increase hepatic cell proliferation, to decrease serum cholesterol, and to increase serum triglycerides. Differentially expressed genes and pathways were identified using Affymetrix GeneChips. Gene-pathway associations were obtained from the Kyoto Encyclopedia of Genes and Genomes, Biocarta, and MetaCore compendia. The pathway profiles of each conazole were different at each time point. In general, the number of altered metabolism, signaling, and growth pathways increased with time and dose and were greatest with propiconazole. All conazoles had effects on nuclear receptors as evidenced by increased expression and enzymatic activities of a series of related cytochrome P450s (CYP). A subset of altered genes and pathways distinguished the three conazoles from each other. Triadimefon and propiconazole both altered apoptosis, cell cycle, adherens junction, calcium signaling, and EGFR signaling pathways. Triadimefon produced greater changes in cholesterol biosynthesis and retinoic acid metabolism genes and in selected signaling pathways. Propiconazole had greater effects on genes responding to oxidative stress and on the IGF/P13K/AKt/PTEN/mTor and Wnt-beta-catenin pathways. In conclusion, while triadimefon, propiconazole, and myclobutanil had similar effects in mouse liver on hepatomegaly, histology, CYP activities, cell proliferation, and serum cholesterol, genomic analyses revealed major differences in their gene expression profiles.
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PMID:Transcriptional profiles in liver from mice treated with hepatotumorigenic and nonhepatotumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil. 1717 88

Mitochondrial dysfunction is an important cause of metabolic disorders of children and adults, with no effective therapy options. Recently, induction of mitochondrial biogenesis, by transgenic overexpression of PGC1-alpha [peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1-alpha], was reported to delay progression of early-onset cytochrome-c-oxidase (COX) deficiency in skeletal muscle of two mouse models: a muscle-specific knock-out of COX10 (COX10-mKO) and a constitutive knock-out of Surf1 (Surf1-KO). A pan-PPAR agonist, bezafibrate, could similarly delay myopathy progression in COX10-mKOs, but not in SURF1-KOs. We asked whether bezafibrate affected disease progression in late-onset adult-type mitochondrial myopathy mice. These 'Deletor mice' express a dominant patient mutation in Twinkle-helicase, leading to accumulation of multiple mtDNA deletions and subsequent progressive respiratory chain (RC) deficiency with COX-negative muscle fibers at 12 months of age. The primary and secondary molecular findings in Deletor mice mimic closely those in patients with Twinkle myopathy. We applied 0.5% bezafibrate diet to Deletors for 22 weeks, starting at disease manifestation, mimicking patient treatment after diagnosis. Bezafibrate delayed significantly the accumulation of COX-negative fibers and multiple mtDNA deletions. However, mitochondrial biogenesis was not induced: mitochondrial DNA copy number, transcript and RC protein amounts decreased in both Deletors and wild-type mice. Furthermore, bezafibrate induced severe lipid oxidation effects, with hepatomegaly and loss of adipose tissue, the mechanism involving lipid mobilization by high hepatic expression of FGF21 cytokine. However, as bezafibrate has been tolerated well by humans, the beneficial muscle findings in Deletor mice support consideration of bezafibrate trials on adult patients with mitochondrial myopathy.
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PMID:Effect of bezafibrate treatment on late-onset mitochondrial myopathy in mice. 2201 83

Perfluorooctane sulfonate (PFOS), a hepatotoxic pollutant, is detected in the human cord blood, and it may induce health risk to an embryo. In this study, we established intrauterine exposure to PFOS in mice to evaluate potential impacts of PFOS on postnatal day 1 (PND1) offspring through conducting biochemical tests, quantitative PCR, and immunostaining. As results, PFOS-exposed maternal mice showed marked hepatomegaly and induced liver steatosis in a high dose of 5 mg PFOS/kg. In PND1 mice, intrahepatic contents of triglyceride, total cholesterol, and LDL were elevated by high-dose PFOS exposure, while intracellular HDL content was decreased. As shown in quantitative PCR, functional messenger RNAs of cytochrome P4A14 (CYP4A14) for fatty acid oxidation, CD36 for hepatic fatty acid uptake, and apolipoprotein B100 (APOB) and fibroblast growth factor 21 (FGF21) for hepatic export of lipids in PND1 livers were changed when compared to those in PFOS-free controls. In further validations, immunofluorescence stains showed that hepatic CYP4A14 and CD36 immunoreactive cells were increased in PFOS-exposed PND1 mice. In addition, reduced immunofluorescence-positive cells of APOB and FGF21 were observed in PND1 livers. Collectively, these preliminary findings demonstrate that prenatal exposure to PFOS may affect lipid metabolism in liver cells of PND1 mice.
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PMID:Effect of prenatal PFOS exposure on liver cell function in neonatal mice. 3104 7

Based on a review of species mortalities, systemic Isospora species was identified as the primary cause of death in 22% (19 of 87) of blue-crowned laughing thrushes (BCLTs; Garrulax courtoisi) at the Jersey Zoo between 1997 and 2016. Fifty-eight percent of the affected birds were between 1 and 2 years old, and in 89% of cases, death occurred between August and December. Abnormal clinical findings in BCLTs with Isospora species infections included hepatomegaly and pectoral muscle myositis in 79% of the cases. The results of diagnostic blood testing in 90% of infected BCLTs 30 days before death were consistent with a severe leukocytosis with greater than 20% of mononuclear cells infected by merozoites. The most common lesions identified during gross necropsy examination were splenomegaly (100%), hepatomegaly (95%), and multifocal, raised, white foci in pectoral (84%) and heart (79%) muscle. Lymphohistiocytic inflammation was identified in the liver, heart, spleen, lung, striated muscle, and kidney tissue of birds with positive results for Isospora species. Merozoites were often observed in spleen, liver, pectoral muscle, and hearts of infected BCLTs. Polymerase chain reaction diagnostic testing that targeted the cytochrome c oxidase subunit, followed by Sanger sequencing, was used to confirm Isospora species in all 14 birds tested. Of samples tested, the highest genetic correlation was with GenBank accession number KT203397 (Isospora species JRB-2016 mitochondrion).
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PMID:Clinical and Pathological Aspects of Systemic Isospora Infection in Blue-crowned Laughing Thrushes (Garrulax courtoisi) at Jersey Zoo. 3189 22


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