Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Deoxy-D-galactose, in a dose of 3 mmol/kg, was administered intraperitoneally twice daily to young rats for periods up to 12 weeks. This dosage schedule resulted in recurrent phosphate trapping predominantly in liver. UTP deficiency was excluded by simultaneous uridine injections. Phosphate trapping was caused by the rapid accumulation of 2-deoxy-D-galactose 1-phosphate and was most pronounced in liver but also demonstrated in small intestine, brain, spleen, and thymus. The marked, although transient, drop in the hepatic content of inorganic phosphate triggered the catabolism of adenine nucleotides and a loss of ATP. Other metabolic pathways affected by phosphate deficiency include glycogenolysis and glycolysis. Increasing with time, repeated doses of the galactose analog led to retardation and arrest of growth, hepatomegaly, and splenomegaly. The average relative liver and spleen weights were elevated 2.5- and 4.5-fold, respectively, after 12 weeks of treatment. Liver damage was indicated by hyperbilirubinaemia and a progressive rise in the activity in plasma of sorbitol dehydrogenase, alkaline phosphatase, and gamma-glutamyltransferase. Examination by light and electron microscopy showed increasing numbers of vacuoles, surrounded by a single membrane, in hepatocytes, sinusoidal endothelial cells, and Kupffer cells. Focal cytoplasmic degeneration in hepatocytes was occasionally indicated by formation of autophagic vacuoles and finger print lysosomes. Hepatocytes of 2-deoxy-D-galactose-treated rats showed a dissociation and fragmentation of the rough endoplasmic reticulum. Sinusoidal endothelial cells and Kupffer cells were markedly enlarged, the latter contained a PAS-positive but amylase resistant substance. Extrahepatic changes included an increased occurrence of vacuolated cells in thymus. Phosphate trapping and its metabolic consequences are common phenomena in the experimental injury induced b 2-deoxy-D-galactose and in some hereditary diseases such as uridylyltransferase deficiency galactosaemia, fructose intolerance and glucose-6-phosphatase deficiency.
Virchows Arch B Cell Pathol Incl Mol Pathol 1979 Jun 29
PMID:Consequences of recurrent phosphate trapping induced by repeated injections of 2-deoxy-D-galactose. Biochemical and morphological studies in rats. 4 10

Dehydroepiandrosterone (DHEA), administered per os, serves to prevent or retard the development of a variety of genetic and induced disorders in mice and rats. This treatment also results in the development of hepatomegaly, a change of liver color from pink to mahogany, peroxisome proliferation in hepatocytes and alterations in hepatocyte mitochondria morphology and respiration. We used one- and two-dimensional polyacrylamide gel electrophoresis (PAGE) to identify changes in the relative levels of liver proteins produced by DHEA treatment of rodents. In mouse liver, there were apparent increases in the levels of 26 proteins and decreases in the levels of 7 proteins. Of the induced proteins the most prominent had Mr approximately 72 K; this protein was identified in a previous study as enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase. Another protein of Mr approximately 28 K, of unknown nature, also was induced markedly by DHEA treatment of mice and rats. A protein of Mr approximately 160 K, which was identified as carbamoyl phosphate synthetase-I (CPS-I), was decreased markedly by DHEA action. This enzyme, which comprises approx. 15-20% of mitochondrial matrix protein, is involved in the entry and rate-limiting step of the urea cycle. The specific activity of CPS-I also was significantly decreased by DHEA, but serum urea levels were normal. To determine whether steroids other than DHEA also induced similar changes, mice were treated with various steroids for 14 days and, thereafter, liver proteins were evaluated by SDS-PAGE: estradiol-17 beta and isoandrosterone induced both the approximately 72 and approximately 28 kDa proteins, testosterone and androsterone induced the 28 kDa protein only, but etiocholanolone, pregnenolone and progesterone were without effect. The findings of this study serve to demonstrate that: (i) hepatic protein levels are affected by DHEA treatment of mice and rats; (ii) liver CPS-I activity is decreased significantly by DHEA treatment, but serum urea levels remain within the normal range; and (iii) sex steroids and some of their precursors, when administered per os, also alter liver protein levels.
J Steroid Biochem Mol Biol 1991 May
PMID:Inhibition of carbamoyl phosphate synthetase-I by dietary dehydroepiandrosterone. 182 77

Previously, we have established that some peroxisome proliferators, a class of nongenotoxic hepatocarcinogens, are able to induce replicative DNA synthesis (RDS) in cultured hepatocytes. Hepatomegaly observed after short-term in vivo treatment correlated better with the ability to induce RDS than with the potency as peroxisome proliferator assessed in vitro. To clarify the challenging question of the limited sensitivity of primates to peroxisome proliferators, primary cultures of marmoset hepatocytes have been treated with nafenopin for some days. As expected from in vivo observations, no evidence for peroxisome proliferation could be observed. However, nafenopin induced a dose-dependent increase in the amount of RDS, but this induction was measurable only when the serum was absent from the culture medium. These results confirm that peroxisome proliferation and mitogenicity might be independent properties of peroxisome proliferators. Since in vivo the ability of compounds to induce RDS in liver cells is relevant to at least one key parameter of the hepatocarcinogenic response, it is suggested that measurement of RDS inducibility in cultured hepatocytes from different species might be relevant and useful to assess species differences in the liver tumor potency of nondirectly genotoxic compounds.
Mol Toxicol
PMID:Assessment of peroxisome proliferation and liver growth-stimulating potential by nondirectly genotoxic compounds in cultured hepatocytes. 315 2

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.
Exp Mol Pathol 1987 Aug
PMID:Biochemical and morphological studies of ammonium perfluorooctanoate-induced hepatomegaly and peroxisome proliferation. 360 46

A newborn female, the second child of consanguineous parents, exhibited general muscle hypotonia, apathy, hepatomegaly and failure to thrive from birth and signs of craniofacial dysmorphia were present. Pipecolic and trihydroxicoprostanoic acid were excreted in the urine and serum transferrin, ferritin and iron were markedly elevated. At the age of 7 weeks the baby died of respiratory insufficiency. Besides malformations of the brain, renal cysts, liver damage with hypoplastic intrahepatic bile ducts and cholestasis, increased storage of iron and cytochemically proven deficiency of peroxisomes in liver and kidney, morphological studied provided evidence of a mitochondrial myopathy in striated muscle with the accumulation of enlarged bizarre mitochondria, showing only minor structural abnormalities. No defects of NADH-reductase, succinate-dehydrogenase or cytochrome-c-oxidase were demonstrated histochemically. Cytochemical-ultrastructural investigation of mitochondrial ATPase revealed activation of the ATP-synthesising enzyme even before the addition of an uncoupler, this indicating loosely coupled oxidative phosphorylation. In addition a high rate of subcellular autophagy with segregation of mitochondria and focal loss of fibrils was present. Muscle damage in Zellweger syndrome appears to be the consequence of complex, interacting metabolic processes. The mitochondrial myopathy thereby induced allows a better understanding of general muscle hypotonia, one of the leading symptoms of this disorder.
Virchows Arch B Cell Pathol Incl Mol Pathol 1984
PMID:Mitochondrial myopathy with loosely coupled oxidative phosphorylation in a case of Zellweger syndrome. A cytochemical-ultrastructural study. 614 41

A low dose of nitrendipine (a calcium antagonist) ameliorated the percentage incidence and severity of cardiac and renal lesions induced by deoxycorticosterone (DOC) despite maintenance of the systolic blood pressure of the DOC plus nitrendipine group in the hypertensive range. The percentage mortality in the DOC-calcium antagonist group was slightly lower than that in the DOC-vehicle injected group. Nitrendipine did not reduce the DOC-induced renal hypertrophy, cardiomegaly, splenomegaly, or hepatomegaly as reflected in the absolute or relative weights of these organs. The absolute and relative weights of the thymus of the nitrendipine-DOC group did not differ significantly from those of controls although these weights decreased significantly in the group receiving DOC. No changes in relative weights of the adrenal gland were observed. The level of calcium in the serum of groups receiving DOC with or without nitrendipine was reduced significantly as compared to the comparable controls. Nitrendipine at the low dose employed separates at least in part the changes exerted by elevated blood pressure in animals receiving DOC from cardiac and renal lesions.
Exp Mol Pathol 1984 Dec
PMID:A low dose of a calcium antagonist (nitrendipine) ameliorates cardiac and renal lesions induced by DOC in the rat. 651 May 6

To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in rodents, we disrupted the ligand-binding domain of the alpha isoform of mouse PPAR (mPPAR alpha) by homologous recombination. Mice homozygous for the mutation lack expression of mPPAR alpha protein and yet are viable and fertile and exhibit no detectable gross phenotypic defects. Remarkably, these animals do not display the peroxisome proliferator pleiotropic response when challenged with the classical peroxisome proliferators, clofibrate and Wy-14,643. Following exposure to these chemicals, hepatomegaly, peroxisome proliferation, and transcriptional-activation of target genes were not observed. These results clearly demonstrate that mPPAR alpha is the major isoform required for mediating the pleiotropic response resulting from the actions of peroxisome proliferators. mPPAR alpha-deficient animals should prove useful to further investigate the role of this receptor in hepatocarcinogenesis, fatty acid metabolism, and cell cycle regulation.
Mol Cell Biol 1995 Jun
PMID:Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. 753 1

X-linked liver glycogenosis (XLG) due to liver phosphorylase kinase (PHK) deficiency is the most frequent liver glycogen storage disease. The affected patients present in early childhood with hepatomegaly and growth retardation. We isolated and determined the structure of human liver alpha subunit of PHK (PHKA2) cDNA. The 3705 base pair open reading frame encodes a polypeptide of 1235 amino acid residues, and the deduced amino acid sequence shows 93 and 68% homology to that of rabbit liver alpha subunit of PHK and human muscle alpha subunit of PHK, respectively. We identified a missense mutation, a valine substitution for glycine at amino acid 193, in the PHKA2 gene of a family with XLG.
Biochem Mol Biol Int 1995 Jul
PMID:Isolation of cDNA encoding the human liver phosphorylase kinase alpha subunit (PHKA2) and identification of a missense mutation of the PHKA2 gene in a family with liver phosphorylase kinase deficiency. 754 48

The effects of ciprofibrate and fenofibrate, which are more potent peroxisome proliferators than clofibrate, on the activities of dihydroxyacetone-phosphate acyl-transferase (DHAP-AT) and glycerol-3-phosphate acyl-transferase (G3P-AT) were studied at the two pH optima 5.5 and 7.4 in subcellular fractions of rat liver, and in solubilized peroxisomal membranes (PMP) as well. Protein was also analyzed by gel electrophoresis. 1) Under the conditions of the specific activity of peroxisomal acyl-CoA oxidase (CN(-)-ACO) being increased (8 to 9-fold), there was no specific induction of the DHAP-AT activity when measured at pH 5.5 in purified peroxisomes and PMP. However, the total activities of DHAP-AT in these two fractions were increased by 6 to 11 times, as a result of hepatomegaly and peroxisome proliferation. In contrast, they were only slightly enhanced (x 1.1 to 2.2-fold) when determined at pH 7.4. The magnitude of the effects of a fibrate treatment was, therefore, dependent on the pH of the incubation medium. 2) Experiments of reversibility of enzyme induction reinforced the finding that the peroxisomal DHAP-AT activity is not specifically induced by ciprofibrate and fenofibrate. 3) Our results suggest the existence of a peroxisomal G3P-AT, non-inducible by fibrates, in the rat liver. 4) Induction of peroxisomal membrane-associated polypeptides with apparent molecular masses of 26- and 36-kDa was evidenced in stained electrophoretic gels of protein.
Cell Mol Biol (Noisy-le-grand) 1993 Feb
PMID:Effects of two peroxisome proliferators (ciprofibrate and fenofibrate) on peroxisomal membrane proteins and dihydroxyacetone-phosphate acyl-transferase activity in rat liver. 846 41

X-linked liver glycogenosis type II (XLG II) is a recently described X-linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.
Hum Mol Genet 1996 May
PMID:X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase. 873 33


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