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)

A study was performed to determine whether diclofop (2-(4-(2,4-dichlorophenoxy) phenoxy)propionic acid), introduced as a herbicide, exhibits the properties of peroxisome proliferators (PPs). Diclofop was administered orally at 7-56 mg/kg body weight per day to male Wistar rats for 2, 4, 7 or 14 consecutive days and some effects regarded as early hepatic markers of PPs were studied. The early changes in rat liver, produced by short-term treatment with diclofop consisted of mitogenesis and, time- and dose-related increase in liver weight. Hepatomegaly was typically associated with proliferation of smooth endoplasmic reticulum (SER) and peroxisomes. The parallel biochemical measurements showed that there was a dose-dependent increase in peroxisomal palmitoyl-CoA oxidation and catalase activity in treated rats. Markers of hepatocellular proliferation (S- and M-phase) indicated that mitogenesis was transient and declined despite continuation of diclofop treatment. The threshold exposure level for the palmitoyl-CoA oxidation (one of the peroxisome proliferation markers) was approximately the same (14 mg/kg body weightxper day) as for the stimulation of mitogenesis in Wistar rats. However, for hepatomegaly and catalase activity the threshold exposure level was 7 mg/kg body weightxper day. The results presented here demonstrate clearly that diclofop belongs to a class of rodent PPs.
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PMID:Studies of early hepatocellular proliferation and peroxisomal proliferation in Wistar rats treated with herbicide diclofop. 1127 54

Glycogen storage disease type 1 (GSD-1), also known as von Gierke disease, is a group of autosomal recessive metabolic disorders caused by deficiencies in the activity of the glucose-6-phosphatase (G6Pase) system that consists of at least two membrane proteins, glucose-6-phosphate transporter (G6PT) and G6Pase. G6PT translocates glucose-6-phosphate (G6P) from cytoplasm to the lumen of the endoplasmic reticulum (ER) and G6Pase catalyzes the hydrolysis of G6P to produce glucose and phosphate. Therefore, G6PT and G6Pase work in concert to maintain glucose homeostasis. Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Both manifest functional G6Pase deficiency characterized by growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, and lactic acidemia. GSD-1b patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, resulting in recurrent bacterial infections as well as ulceration of the oral and intestinal mucosa. The G6Pase gene maps to chromosome 17q21 and encodes a 36-kDa glycoprotein that is anchored to the ER by 9 transmembrane helices with its active site facing the lumen. Animal models of GSD-1a have been developed and are being exploited to delineate the disease more precisely and to develop new therapies. The G6PT gene maps to chromosome 11q23 and encodes a 37-kDa protein that is anchored to the ER by 10 transmembrane helices. A functional assay for the recombinant G6PT protein has been established, which showed that G6PT functions as a G6P transporter in the absence of G6Pase. However, microsomal G6P uptake activity was markedly enhanced in the simultaneous presence of G6PT and G6Pase. The cloning of the G6PT gene now permits animal models of GSD-1b to be generated. These recent developments are increasing our understanding of the GSD-l disorders and the G6Pase system, knowledge that will facilitate the development of novel therapeutic approaches for these disorders.
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PMID:The molecular basis of type 1 glycogen storage diseases. 1189 41

Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. The two major subtypes are GSD-Ia (MIM232200), caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib (MIM232220), caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Both G6Pase and G6PT are associated with the endoplasmic reticulum (ER) membrane. G6PT translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the ER, where G6Pase hydrolyses the G6P into glucose and phosphate. Together G6Pase and G6PT maintain glucose homeostasis. G6Pase is expressed in gluconeogenic tissues, the liver, kidney, and intestine. However G6PT, which transports G6P efficiently only in the presence of G6Pase, is expressed ubiquitously. This suggests that G6PT may play other roles in tissues lacking G6Pase. Both GSD-Ia and GSD-Ib patients manifest phenotypic G6Pase deficiency, characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic academia and the current treatment is a dietary therapy. GSD-Ib patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, which is treated with granulocyte colony stimulating factor to restore myeloid function. The GSD-Ia and GSD-Ib genes have been cloned. To date, 76 G6Pase and 69 G6PT mutations have been identified in GSD-I patients. A database of the residual enzymatic activity retained by the G6Pase missense mutants is facilitating the correlation of the disease phenotype with the patients' genotype. While the molecular basis for the GSD-I disorders are now known and symptomatic therapies are available, many aspects of the diseases are still poorly understood, and there are no cures. Recently developed animal models of the disorders are now being exploited to delineate the disease more precisely and develop new, more causative therapies.
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PMID:Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. 1194 31

The aim of this study was to determine the effect of herbicide fluazifop, on the early occurring changes in rat liver regarded as hepatic markers of peroxisome proliferators (PPs). Fluazifop was administered orally to male Wistar rats at increasing doses from 5.6 to 891 mg/kg body weight per day for 1, 2, 4, 7 and 14 consecutive days and peroxisome proliferation, induction of some peroxisome-associated enzymes and mitogenesis (S-phase, M-phase and percentage of binucleated hepatocytes) were studied. Short-term treatment of rats with fluazifop resulted in hepatomegaly due to time dependent proliferation of smooth endoplasmic reticulum (SER) and peroxisomes. The increase in the number of peroxisomes in the hepatocytes was supported by an increase in peroxisomal palmitoyl-CoA oxidation and catalase activity. In contrast to other PPs fluazifop induced low rate of rcplicative DNA synthesis and did not affect mitoses (M-phase). DNA synthesis was accompanied by the appearance of binucleated hepatocytes. Thus, we can conclude that fluazifop produces in male Wistar rats hepatomegaly due to cellular hypertrophy. The threshold dose for palmitoyl-CoA oxidation and DNA synthesis was 112 and 223 mg/kg body weight per day, respectively. The value for hepatomegaly and catalase activity was 56 mg/kg body weight per day. The results presented in this paper demonstrated that fluazifop can be classified as a weak rodent PPs.
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PMID:Hepatocellular peroxisome proliferation and DNA synthesis in Wistar rats treated with herbicide fluazifop. 1216 8

Deficiency of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, causes glycogen storage disease type Ia (GSD-Ia), an autosomal recessive disorder characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. G6Pase is an endoplasmic reticulum-associated transmembrane protein expressed primarily in the liver and the kidney. Therefore, enzyme replacement therapy is not feasible using current strategies, but somatic gene therapy, targeting G6Pase to the liver and the kidney, is an attractive possibility. Previously, we reported the development of a mouse model of G6Pase deficiency that closely mimics human GSD-Ia. Using neonatal GSD-Ia mice, we now demonstrate that a combined adeno virus and adeno-associated virus vector-mediated gene transfer leads to sustained G6Pase expression in both the liver and the kidney and corrects the murine GSD-Ia disease for at least 12 months. Our results suggest that human GSD-Ia would be treatable by gene therapy.
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PMID:Sustained hepatic and renal glucose-6-phosphatase expression corrects glycogen storage disease type Ia in mice. 1218 68

A twenty year old, foreign-born sportsman visited the Out-patient Clinic of our Hospital with complaints of progressive arthralgia, hepatomegaly and increasingly abnormal liver function tests of six months duration. Tests for virus hepatitis were negative, alcohol abuse or drug addiction could be excluded. An open needle biopsy of the liver was performed and the tissue was examined with the light and electron microscope. On routine light microscopy no abnormality was recognized. Electron microscopic examination revealed changes characteristic of vitamin A toxicity: hyperplasia of the perisinusoidal (Ito) cells with evidence of their activation and transformation, increased storage of lipids and vitamin A, perisinusoidal fibrosis, damage of the sinusoidal wall, partial necrosis in hepatocytes and an increased number of lysosomes, megalysosomes and smooth endoplasmic reticulum (SER), the signs of cholestasis as well as an increased number of Kupffer cells in the lobules etc. Histochemical examination showed a high content of vitamin A in the transitional (Ito) cells and in hepatocytes. These data led to further questioning of the patient who disclosed that he had acne conglobata which had been treated with Isotretionin, 20 mg/day, for more than half a year. After the therapy was stopped, the symptoms of polyarthralgia improved and after a few months they ceased entirely, however, the laboratory data returned to normal only after a long period of time. This case indicates that electron microscopic examination of the liver biopsy may play an important role in the recognition of vitamin A intoxication. It also illustrates that symptoms of joint disease may be caused by long-term retinoid treatment. The authors have presented the latest clinical and experimental data concerning the changes in the liver, joints and skeleton caused by retinoid intoxication.
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PMID:[Ultrastructural findings in the liver due to long-term retinol (isotretinoin) treatment. Significance of the perisinusoidal (Ito) cells]. 1497 83

Three hundred day-old Japanese quail (Coturnix coturnix japonica) were divided into two groups with 150 quail in each group. One group was maintained on quail mash alone, while Fusarium moniliforme culture material was added to quail mash in the second group from day 5 of age and was supplied at a rate of 150 ppm fumonisin B1 (FB1)/kg mash. At day 21, each group was further subdivided into two groups, yielding four groups with 75 birds apiece, which served as the control (group CX), the Salmonella Gallinarum alone group (group CS), the FB1 alone group (group FX), and the group fed FB1 and infected with Salmonella Gallinarum (group FS). An oral challenge with Salmonella Gallinarum organisms (2 x 10(4) colony-forming units/ml) was given to groups CS and FS at 21 days of age. Three quail each were necropsied on day 21 (0 day interval) from groups CX and FX only. At subsequent intervals (i.e., 1, 2, 3, 5, 7, 10, 14, and 21 days postinfection [DPI]), three quail were euthanatized from all four groups (CX, CS, FX, and FS). The gross and microscopic lesions were recorded in both mortality and euthanatized birds at the above intervals. The ultrastructural studies were done at 5 DPI. Mild to moderate hepatomegaly and pale discoloration of liver were observed in group FX, while congestion, hemorrhages, necrosis, and mild to severe hepatomegaly were the predominant gross lesions in both infected groups (CS and FS). The gross lesions in quail inoculated with Salmonella Gallinarum alone (group CS) generally developed slowly, appeared more widely scattered, and involved comparatively less surface area in contrast to the rapidly progressive and frequently confluent lesions in the combination group (FS), especially in the first 5 days of infection. Mild to marked hepatocellular swelling, multifocal hepatic necrosis, and hepatocellular and bile duct hyperplasia were the characteristic microscopic changes in the FX group. Microscopic lesions in quail of group CS comprised congestion, vacuolar changes, and focal necrosis in early stages, followed by granulomatous lesions at later intervals. Similar but more severe lesions were observed in the combination group (FS). Based on transmission electron microscopy, the maximum effect of FB1 toxicity was observed on mitochondria and endoplasmic reticulum. In general, the mitochondriae showed diverse form and structure, some of which appeared to lose their intact outer membrane, and the mitochondrial cristae were disoriented. The deformity in the cisternae structure of rough endoplasmic reticulum, with their rearrangement into round or tubular forms either bearing granular surface or leading to accumulation of smooth endoplasmic reticulum, was evident only in groups FX and FS. We conclude that the continuous presence of fumonisins in the diets of young quail might increase their susceptibility to or the severity of Salmonella Gallinarum infection.
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PMID:Individual and combined effects of Fusarium moniliforme culture material, containing known levels of fumonisin B1, and Salmonella gallinarum infection on liver of Japanese quail. 1640 6

Niemann-Pick type C1 (NPC1) disease is an autosomal-recessive cholesterol-storage disorder characterized by liver dysfunction, hepatosplenomegaly, and progressive neurodegeneration. The NPC1 gene is expressed in every tissue of the body, with liver expressing the highest amounts of NPC1 mRNA and protein. A number of studies have now indicated that the NPC1 protein regulates the transport of cholesterol from late endosomes/lysosomes to other cellular compartments involved in maintaining intracellular cholesterol homeostasis. The present study characterizes liver disease and lipid metabolism in NPC1 mice at 35 days of age before the development of weight loss and neurological symptoms. At this age, homozygous affected (NPC1(-/-)) mice were characterized with mild hepatomegaly, an elevation of liver enzymes, and an accumulation of liver cholesterol approximately four times that measured in normal (NPC1(+/+)) mice. In contrast, heterozygous (NPC1(+/-)) mice were without hepatomegaly and an elevation of liver enzymes, but the livers had a significant accumulation of triacylglycerol. With respect to apolipoprotein and lipoprotein metabolism, the results indicated only minor alterations in NPC1(-/-) mouse serum. Finally, compared to NPC1(+/+) mouse livers, the amount and processing of SREBP-1 and -2 proteins were significantly increased in NPC1(-/-) mouse livers, suggesting a relative deficiency of cholesterol at the metabolically active pool of cholesterol located at the endoplasmic reticulum. The results from this study further support the hypothesis that an accumulation of lipoprotein-derived cholesterol within late endosomes/lysosomes, in addition to altered intracellular cholesterol homeostasis, has a key role in the biochemical and cellular pathophysiology associated with NPC1 liver disease.
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PMID:Characterization of liver disease and lipid metabolism in the Niemann-Pick C1 mouse. 1721 1

Glucose-6-phosphatase-alpha (G6PC) is a key enzyme in glucose homeostasis that catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis. Mutations in the G6PC gene, located on chromosome 17q21, result in glycogen storage disease type Ia (GSD-Ia), an autosomal recessive metabolic disorder. GSD-Ia patients manifest a disturbed glucose homeostasis, characterized by fasting hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation. G6PC is a highly hydrophobic glycoprotein, anchored in the membrane of the endoplasmic reticulum with the active center facing into the lumen. To date, 54 missense, 10 nonsense, 17 insertion/deletion, and three splicing mutations in the G6PC gene have been identified in more than 550 patients. Of these, 50 missense, two nonsense, and two insertion/deletion mutations have been functionally characterized for their effects on enzymatic activity and stability. While GSD-Ia is not more prevalent in any ethnic group, mutations unique to Caucasian, Oriental, and Jewish populations have been described. Despite this, GSD-Ia patients exhibit phenotypic heterogeneity and a stringent genotype-phenotype relationship does not exist.
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PMID:Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. 1844 99

Antiepileptic agents are known to cause adverse effects in human liver, including steatosis. Clobazam (CLB), a 1,5-benzodiazepine, is clinically used as an antiepileptic agent. In the previous study, 4-week treatment with CLB induced hepatomegaly in male rats. In the present study, the human risk of hepatomegaly was assessed and the causative mechanism in terms of cell proliferation and apoptosis, oxidative stress, and drug-metabolizing enzyme induction was elucidated by toxicological approach. Male SD rats were treated orally with 400 mg/kg CLB for 1, 3, 7, 14, or 28 days. The 28-day treatment was followed by 7 or 14 days of withdrawal. At the end of each treatment, the liver and plasma of each rat were examined. Liver weight increased from Day 3 of CLB treatment. This increase was mostly accompanied by hepatic centrilobular hypertrophy and proliferation of smooth endoplasmic reticulum (SER), and by an increase in microsomal proteins. Cyp2b1, Cyp3a1, Cyp3a2, and Ugt2b2 mRNA levels in the liver were upregulated as compared to the control group throughout the dosing period. On the other hand, the thiobarbituric acid reactive substance (TBARS) formulation, hepatocyte proliferation, and apoptosis, assumed to play roles in laying groundwork for effective induction of metabolizing enzymes, were increased only at the acute phase of treatment. These results suggested that CLB-induced hepatomegaly in male rats is mainly attributable to microsomal enzyme induction associated with Cyp2b1, Cyp3a1, Cyp3a2, and Ugt2b2 gene upregulation, but does not cause any toxicological concerns.
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PMID:Toxicological approach for elucidation of clobazam-induced hepatomegaly in male rats. 2157 66


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