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)

Peroxisome proliferators (PP) are a diverse group of chemicals that induce dramatic increases in peroxisomes in rodent hepatocytes, followed by hypertrophy, hepatomegaly, alterations in lipid metabolism, mitogenesis, and finally hepatocarcinomas. Termed nongenotoxic carcinogens, they do not interact with DNA, are not mutagenic in bacterial assays, and fail to elicit many of the phenotypes associated with classic genotoxic carcinogens. We report here that the mitogenesis induced by the major PP class, the amphipathic carboxylates, and by the tetrazole-substituted acetophenones specifically requires liver fatty acid-binding protein (L-FABP) in cultured rat hepatoma cells transfected with the sense cDNA of L-FABP, in contrast to L-FABP-nonexpressing cells transfected with its antisense cDNA. The mitogenic actions of L-FABP were protein-specific, inasmuch as no other protein in the nonexpressing cells could act like L-FABP. L-FABP was previously shown not only (i) to interact covalently with metabolites of the two genotoxic carcinogens 2-acetylaminofluorene and aminoazo dyes during liver carcinogenesis, but also (ii) to bind noncovalently the two classes of PP in vitro with avidities that correlate with their abilities to elicit peroxisomal enzymatic responses, and (iii) together with unsaturated fatty acids, especially linoleic acid, to promote multiplication of the transfected hepatoma cells in culture. The convergence of the two types of genotoxic carcinogens with the two classes of PP nongenotoxic carcinogens, and also with unsaturated fatty acids, at L-FABP actions in inducing mitogenesis allows the following hypothesis. During tumor promotion of carcinogenesis in vivo, these groups of genotoxic and nongenotoxic carcinogens act on the normal process by which L-FABP, functioning as a specific receptor of unsaturated fatty acids or their metabolites, promotes hepatocyte proliferation.
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PMID:Liver fatty acid-binding protein: specific mediator of the mitogenesis induced by two classes of carcinogenic peroxisome proliferators. 830 56

Classical galactosaemia, deficiency of galactose-1-phosphate uridyltransferase (GALT), is characterized by acute symptoms of hepatomegaly, jaundice, sepsis, cataracts and growth retardation. Treatment with dietary galactose restriction corrects these complications immediately; however, most of these children develop long-term complications of verbal dyspraxia, mental retardation and ovarian failure. Our previous molecular study showed that the most common mutation of the GALT gene is a missense mutation of Q188R (replacement of glutamine-188 by arginine) in approximately 60-65% of the German galactosaemic population. The coding region of GALT was amplified by the polymerase chain reaction from genomic DNA of classical galactosaemic individuals, who are negative or heterozygous for Q188R, and was further characterized by direct sequencing. Three new disease-causing mutations, two missense and a stop codon mutation, were identified in three patients from two families with mild galactosaemic variants: firstly R67C, replacement of arginine-67 by cysteine and W316X, the stop codon at tryptophan-316 in one male; secondly A330V, replacement of alanine-330 by valine in two female siblings. In the first family the patient was also heterozygous for the polymorphism N314D and in the second family both girls were compound heterozygotes for Q188R and A330V. All three galactosaemic individuals have a considerable amount of the residual GALT activity in RBC and the galactose-1-phosphate (GALP) level decreased much faster on treatment than that of other galactosaemic patients with missense mutations such as Q188R. The clinical and biochemical data of these patients were much more favourable in comparison with those of two female galactosaemic individuals, one homozygous for L195P and the other compound heterozygous for Q188R and L195P. These three missense mutations (R67C, L195P and A330V) also occur in highly conserved regions. These observations suggest that the phenotypic variation in galactosaemic individuals may be due to different molecular aetiologies.
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PMID:Mutations in the galactose-1-phosphate uridyltransferase gene of two families with mild galactosaemia variants. 859 37

The aim of the present studies was to describe the effect of two organohalogen pesticides: DDT and bromopropylate, on early changes in rat liver, proposed in the literature to be useful endpoints in screening of non-genotoxic hepatocarcinogens and/or liver tumor promoters. We investigated the effects on the following endpoints: hepatomegaly, mitogenesis (DNA synthesis, mitotic activity, percentage of binuclear cells) and cytochrome CYP2B1-dependent monooxygenase induction. The histological and cytochemical changes in the liver were also recorded. Male Wistar rats received bromopropylate in one, three or five daily oral doses of 125, 250, and 500 mg/kg body wt. day-1. DDT was applied as one, three, and five daily oral doses of 24 mg/kg body wt. day-1 (this dose is close to the mean hepatocarcinogenic dose in male Wistar rats: 34.1 mg/kg body wt. day-1). In the case of both pesticides the early effects observed consisted of hepatomegaly accompanied by an increase in the p-nitroanisole O-demethylase activity and hepatocyte proliferation. Hepatocyte proliferation was elevated during the total experimental period. Vacuolated cytoplasm and evident focal necrosis may suggest that the maximal increase in hepatocyte proliferation, preceding hepatomegaly, is at least partly related to a regenerative liver response to pesticides. In addition to the above-mentioned early changes, the present findings provide new evidence for the occurrence of dose-dependent abnormal mitoses (and c-mitoses) in the hepatocytes of the bromopropylate and DDT treated rats.
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PMID:Early hepatic changes induced in rats by two hepatocarcinogenic organohalogen pesticides: bromopropylate and DDT. 863 Nov 24

Over 100 marketed drugs induce neoplasia when administered at high doses to rats and mice for periods of up to two years. Despite their diverse chemical structures and biological activities, these compounds produce a relatively limited range of tumour types in rodents, most commonly in the liver. Tumours usually develop only after long periods of time following high exposure to drug. The main exceptions are DNA-reactive anticancer drugs such as alkylating agents which produce tumours rapidly in rodents in several organs. In this laboratory, mouse carcinogenicity studies are performed using the C57BL/10J strain. This strain infrequently develops hepatic tumours spontaneously but it is sensitive to the effects of DNA-reactive carcinogens. Moreover, hepatic neoplasms regularly develop in male but not female C57BL/10J mice following long-term treatment with nongenotoxic drugs that produce hepatic enlargement associated with diverse hepatocellular effects. Studies in this strain with the tumorigenic liver enlarger, phenobarbitone, have shown that although such liver enlargement is characterised by a brief burst of hepatocyte replication, this is associated with persistent regional modulation of hepatic growth stimulatory and inhibitory factors and their associated receptors. These findings indicate that there is a sustained alteration to the internal hepatic environment characterised by regional alterations to the balance of hepatocyte mitogens and inhibitors of replication and their respective receptors. Thus, the development of hepatocellular tumours in C57BL/10J mice following two-year treatment with nongenotoxic drugs appears to be a regular response of an organ to an exaggerated and long-term disruption of its homeostasis. Agents that produce tumours in rodents in this way seem likely to pose little or no risk to humans if administered under appropriate clinical circumstances at doses which show no significant disruption of organ homeostasis. However, drugs that produce this type of response need to be distinguished from those that induce unusual and rapid patterns of tumour development because these agents may have high tumorigenic potency of potential hazard to humans.
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PMID:The evaluation of potential human carcinogens: a histopathologist's point of view. 867 71

Papulonecrotic tuberculid (PNT), a form of cutaneous tuberculosis (TB), is uncommon in children. We identified eight children (six girls and two boys) with PNT. Their ages ranged from 19 to 139 months (median 47.5 months, mean:64.75 months). Skin lesions had been present for 2-24 weeks (median: 4 weeks) before diagnosis. All patients displayed scattered papulo- and/or pustulonecrotic lesions on the limbs, and the ears were involved in six patients. Lesions healed with varioliform scars. Associated pulmonary TB was present in seven patients. Additional clinical findings included fever (n = 4), hepatomegaly (n = 4), lymphadenopathy (n = 3), phlyctenular conjunctivitis (n = 3), and splenomegaly (n = 2). Histology of eight biopsies showed ulceration (n = 6), dermal necrosis (n = 6) (follicle-centered in two), granulomatous inflammation (n = 6) (palisading granuloma-like in three), superficial and deep infiltrate of lymphocytes (n = 7), erythrocyte extravasation (n = 7), and subepidermal edema (n = 3). Vasculitis was not a feature. A Ziehl-Neelsen stain was negative in all. Glycosaminoglycans were not increased. Immunohistochemistry found a predominance of T lymphocytes, macrophages, a few antigen-presenting cells, and no B lymphocytes, consistent with a type IV hypersensitivity reaction. Polymerase chain reaction (PCR) performed on deparaffinized tissue identified M. tuberculosis DNA in one biopsy. All patients received combination anti-TB treatment for 6 months. Six patients were compliant and were followed up for 6-30 months. Skin lesions and pulmonary TB healed in all. PNT in children resembles the adult form, but phlyctenular conjunctivitis and associated TB are more common, scrofuloderma and concomitant erythema induratum of Bazin are unusual, and vasculitis is not found. In cases where M. tuberculosis DNA can be confirmed with PCR, papulonecrotic TB is perhaps the more appropriate nomenclature.
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PMID:Papulonecrotic tuberculid in children. A report of eight patients. 873 93

The aim of present studies was to describe the effect of two organochlorine pesticides: nuarimol and DDT on the changes in rat liver, proposed in the literature to be useful endpoints in screening of non-genotoxic hepatocarcinogens and/or liver tumor promoters. The effects on the following endpoints: mitogenesis (DNA synthesis and mitotic activity), hepatomegaly as well as histological changes in rat liver have been investigated. Male Wistar rats received nuarimol or DDT in one, five and fourteen daily oral administration of the doses of 125 and 12 mg/kg b.w. day-1 respectively. In the case of both pesticides the effects observed consisted of hepatomegaly and hepatocyte proliferation (DNA synthesis and mitotic activity), although our studies indicated several distinct differences in the hepatic response between nuarimol, on the one hand and DDT on the other. The differences were reflected in the character and the basal rate of hepatocyte proliferation. Nuarimol elicited rapid but transient wave of hepatocyte proliferation during the first day of exposure. As opposite to nuarimol, DDT induced sustained hepatocyte proliferation during experimental period (14 days). Moreover, DDT induced evident focal necrosis and abnormal mitoses whereas nuarimol caused only slight vacuolated cytoplasm. Thus it can be concluded that nuarimol induced in rat liver direct mitogenic effect. On the other hand, DDT which is well known hepatocarcinogen, was found to produce mitogenic effect appearing to be related to regenerative response, since histological signs of necrosis were apparent.
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PMID:[The effect of selected polychlorinated hydrocarbon pesticides on proliferation of cells in rat liver (14 day experiment)]. 875 48

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

Glycogen storage disease type III (GSD-III) is an autosomal recessive disease resulting from deficient glycogen debranching enzyme (GDE) activity. A child with GDE deficient in both liver and muscle (GSD-IIIa) had recurrent hypoglycemia, seizures, severe cardiomegaly, and hepatomegaly and died at 4 years of age. Analysis of the GDE gene in this child by single-strand conformation polymorphism, followed by direct DNA sequencing and restriction analysis, revealed an insertion of a nucleotide A into position 4529 of the GDE cDNA (4529insA). This insertion resulted in substitution of a tyrosine to a stop codon at amino acid 1510 (Y1510X). The 4529insA mutation appeared to be homozygous in this patient and was not found in 20 unrelated controls or 18 other GSD-III patients (14 GSD-IIIa and 4 GSD-IIIb). This is the first identification of a disease mutation in this gene, and the data suggest that homozygous 4529insA may be associated with a severe phenotype in GSD-IIIa.
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PMID:A nonsense mutation due to a single base insertion in the 3'-coding region of glycogen debranching enzyme gene associated with a severe phenotype in a patient with glycogen storage disease type IIIa. 899 6

Peroxisome proliferators are believed to induce liver tumors in rodents due to sustained increase in cell proliferation and oxidative stress resulting from the induction of peroxisomal enzymes. The objective of this study was to conduct a sequential analysis of the early changes in cell-cycle kinetics and the dynamics of rat liver DNA synthesis after treatment with a peroxisome proliferator. Immunofluorescent detection of proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) incorporation into DNA during S phase we used to assess rat hepatocyte proliferation in vivo during dietary administration of Wy-14,643, a known peroxisome proliferator and hepatocarcinogen in rodents. Rats were placed on diet containing 0.1% WY-14,643 and implanted subcutaneously with 5-bromo-2'deoxyuridine containing osmotic pumps 4 days prior to being sacrificed on days 4, 11, and 25 of treatment. Isolated liver nuclei labeled with fluorscein isothiocyanate (FITC)-anti-BrdU/PI and FITC-anti-PCNA/PI were analyzed for S-phase kinetics using flow cytometry. Morphometric analysis was performed to evaluate nuclear and cell size and enumeration of BrdU labeled cells, binucleated hepatocytes, and mitotic index. The BrdU labeling index increased 2-fold in livers of Wy-14,643-treated rats at day 4, but distribution of cells in G1, S phase, and G2-M did not differ significantly from controls. PCNA-positive cells decreased from 36% on day 4 to 17% on day 25, whereas the percentage of PCNA-positive cells in controls increased 2-fold from day 4 to day 11 and remained unchanged up to day 25. The differences in the number of PCNA-positive nuclei between control and Wy-14,643-treated groups were statistically significant only on day 4. Binucleated hepatocytes, determined by morphometric analysis, increased slightly on day 25 in treated rats parallel to an increase in the percentage of cells in G2-M phase. Significant shifts were noted in nuclear diameter and nuclear area after 11 and 25 days of treatment with Wy-14,643. Hepatic cell populations with nuclei > 9 microns diameter and nuclear area > 64 microns2 increased in Wy-14,643-fed rats during the treatment period compared with the control, indicating hepatic karyomegaly and hyperploidy, whereas percentage of distribution of nuclei based on diameter and area remained consistently unchanged in control animals from 4 through 25 days of sham treatment. The flow cytometric and morphometric analysis indicated an initial wave of DNA synthesis in response to Wy-14,643. The hepatomegaly was sustained over the treatment period accompanied by increase in ploidy with a significant shift toward hyperploidic hepatocytes. The increase in DNA content was almost entirely accounted for by the overall polypoidy increase rather than by an absolute increase in cells.
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PMID:Increased nuclear ploidy, not cell proliferation, is sustained in the peroxisome proliferator-treated rat liver. 912 75

Two Maltese puppies with massive hepatomegaly and failure to thrive had isolated deficient glucose-6-phosphatase (G-6-Pase) activity in liver and kidney and pathological findings compatible with GSD-Ia. To identify the mutation, we cloned G-6-Pase canine cDNA by RT-PCR with primers from the murine G-6-Pase gene sequence. The canine G-6-Pase cDNA is 2346 bp, with a 5' untranslated region of 87 bp, a coding region of 1071 bp, and a 3' untranslated region of 1185 bp. The difference between the canine and human sequences is in the 3' untranslated region. A greater than 90% amino acid sequence homology was seen with canine, human, murine, and rat G-6-Pase. G-6-Pase cDNA from affected and control puppies revealed complete homology except at nt position 450, which showed a guanine to cytosine (G to C) transversion resulting in substitution of a methionine by isoleucine at codon 121 (M121I) in all five clones studied. The loss of an NcoI restriction site on genomic DNA amplified with primers flanking the mutation allowed us to prove that affected puppies were homozygous for the mutation and parents were heterozygous carriers. The mutant G-6-Pase cDNA had 15 times less enzyme activity than wild-type cDNA following transient transfection. Northern blot analysis of puppies with GSD-Ia revealed increased G-6-Pase mRNA, compared to normal controls. Increased G-6-Pase mRNA was also seen in normal fasted puppies compared to littermates in the fed state, suggesting that the increased G-6-Pase mRNA is a physiologic response to fasting. This is the first report of a molecularly confirmed naturally occurring animal model of GSD-Ia. The establishment of a breeding colony of this dog strain will facilitate studies on the role of G-6-Pase gene in glucose homeostasis, in pathophysiology of disease, and development of novel therapeutic approaches such as gene therapy.
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PMID:Isolation and nucleotide sequence of canine glucose-6-phosphatase mRNA: identification of mutation in puppies with glycogen storage disease type Ia. 925 82


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