Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.9 (glucose-6-phosphatase)
 3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We determined whether alterations in hepatic microsomal function occur in association with iron-induced lipid peroxidation in vivo in rats with chronic dietary iron overload. In rats fed a 2.0% carbonyl iron diet for a period of 20 wk, there was no significant microsomal conjugated diene formation (evidence of microsomal lipid peroxidation) or difference in cytochrome P450 concentration found at mean (+/- SEM) hepatic iron concentrations of 1210 +/- 92 micrograms/g liver (wet wt) or 2730 +/- 100 micrograms/g. At a hepatic iron concentration of 4090 +/- 245 micrograms/g, however, there was significant conjugated diene formation (p less than 0.001) and a 56% decrease in the cytochrome P450 concentration (p less than 0.001). In rats fed a 2.5% carbonyl iron diet for 10 wk, achieving a liver iron concentration of 4820 +/- 420 micrograms/g, there was significant microsomal conjugated diene formation (p less than 0.001), a 35% reduction in cytochrome P450 (p less than 0.005), and a 16% reduction in aminopyrine demethylase activity (p less than 0.025), but only an 8% reduction in glucose-6-phosphatase activity (p = not significant). Finally, in rats fed a 3.0% iron-supplemented diet for 7 wk, achieving a liver iron concentration of 2730 +/- 205 micrograms/g, there was a 23% reduction in cytochrome P450 (p less than 0.025), a 28% reduction in cytochrome b5 (p less than 0.001), and a 47% increase in heme oxygenase activity (p less than 0.025) (heme oxygenase activity measured in this group only). We conclude that oral iron loading can produce microsomal lipid peroxidation in vivo that is associated with selective decreases in microsomal hemoprotein concentrations and cytochrome P450-dependent enzymes.
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PMID:Hepatic microsomal function in rats with chronic dietary iron overload. 300 59

The effects of carbon disulfide (CS2) on the liver microsomal drug-metabolizing enzyme system and other enzyme activities were studied 1 hr after the oral administration of 3-300 mg/kg of CS2 in mice. Considerable decreases in drug-metabolizing enzyme activities (such as hydroxylation of aniline, O-dealkylation of p-nitroanisole, 7-ethoxycoumarin and 7-ethoxyresorufin, and N-demethylation of N,N-dimethylaniline), NADPH-cytochrome P-450 reductase (but not NADPH-cytochrome c reductase), and P-450-associated peroxidase activities were already observed at 3 and 30 mg/kg of CS2, dose dependently. At the same dosage levels, the magnitudes of microsomal spectral changes induced by aniline and nicotinamide (type 2 substrates), but not those induced by hexobarbital and SKF-525A (type 1 substrates), were also reduced to a considerable extent. The degrees of these alterations were all greater than that of the measurable loss of P-450 content, i.e. the loss of functional activity of P-450 was much greater than simply expected from the apparent decrease in the hemoprotein content. Cytochrome b5 content and NADH-ferricyanide reductase activity were unchanged at 30 and 300 mg/kg of CS2, although NADH-cytochrome c reductase activity was increased at the latter dose. The following enzyme activities did not change significantly at up to 300 mg/kg of CS2: flavin-containing monooxygenase, UDP-glucuronyl transferase, glucose-6-phosphatase and heme oxygenase in microsomes, and glutathione S-transferases in the soluble fraction. Microsomal conjugated diene levels and liver glutathione content were also unchanged. These observations support the theory that P-450 is a sensitive and selective site for CS2 action, where CS2 itself is bioactivated. It was also shown that the loss of P-450 was reversible after a single, or repeated, administration of CS2.
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PMID:Early, selective and reversible suppression of cytochrome P-450-dependent monooxygenase of liver microsomes following the administration of low doses of carbon disulfide in mice. 377 18

In rats, surgical creation of a portacaval shunt leads to hepatic atrophy and lowered levels of cytochrome P450, the key component of liver enzymes involved with drug metabolism. These effects are largely attributable to diversion of portal blood away from the liver and not to decreased hepatic blood flow. The present study has established a simpler model of portal blood diversion in order to examine the role of portal blood constituents in the regulation of hepatic cytochrome P450. Portal vein ligation was performed on male Wistar rats in which portasystemic anastomoses had been produced by subcutaneous transposition of the spleen. Portal vein ligation resulted in portal hypertension, as evidenced by splenomegaly, and in hepatic atrophy. In liver of rats with portal vein ligation, microsomal cytochrome P450 levels were significantly less than in sham-operated control rats, but cytochrome b5, NADPH-cytochrome c reductase, and glucose-6-phosphatase were unaltered. The activities of four mixed function oxidases also were reduced significantly in the liver of rats with portal vein ligation, the changes being greatest for ethylmorphine N-demethylase, a prototype substrate for the phenobarbital-inducible isoenzyme of cytochrome P450. In contrast, the activity of microsomal heme oxygenase, the rate-limiting step in catabolism of heme to bilirubin, was enhanced after portal vein ligation. Experiments in pair-fed rats showed that the changes observed in liver from rats with portal vein ligation could not be attributed to caloric deprivation. Administration of phenobarbital increased liver mass, cytochrome P450 levels, and mixed function oxidase activities both in rats with portal vein ligation and in controls, indicating that the liver of the ligated rats retained considerable protein synthetic capacity. It appears that hepatic atrophy and lowering of cytochrome P450 levels that follow portal vein ligation are consequences of altered exposure of the liver to factors normally present in portal blood, and that the same alterations may also enhance heme oxygenase activity.
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PMID:Portal vein ligation selectively lowers hepatic cytochrome P450 levels in rats. 686 53

Toxicological studies of a leachable stabilizer Di-n-butyltin dilaurate (DBTL) were undertaken. Effects of DBTL after 15 days oral exposure to rats were studied on brain and liver enzyme activities. A significant decrease in body weight gain of DBTL exposed rats were observed. No effect was observed in the activities of brain enzymes, succinic dehydrogenase, adenosine triphosphatase, acetylcholine esterase and monoamine oxidase. In liver, DBTL treatment resulted in a significant decrease in the activities of microsomal enzymes glucose-6-phosphatase, aminopyrine-N-demethylase, benzphetamine-N-demethylase, aniline hydroxylase, benzo(a)pyrene hydroxylase and also on cytochrome P-450 content, whereas no difference in the activities of mitochondrial enzymes, succinic dehydrogenase, Mg2+-adenosine triphosphatase as well as in the activity of lysosomal enzyme acid phosphatase was observed. Duration of exposure dependent increase in pentabarbital induced sleeping time was also observed. DBTL treatment produced an induction in heme oxygenase activity whereas the activity of -aminolevulinic acid synthetase remained unaltered. The results demonstrate that DBTL significantly affects the biotransformation mechanism and heme metabolism of hepatocytes.
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PMID:Toxicological studies of a leachable stabilizer di-n-butyltin dilaurate(DBTL): effects on hepatic drug metabolizing enzyme activities. 726 48

We have proposed that hyperglycemia-induced dedifferentiation of beta-cells is a critical factor for the loss of insulin secretory function in diabetes. Here we examined the effects of the duration of hyperglycemia on gene expression in islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats developed different degrees of hyperglycemia; low hyperglycemia was assigned to Px rats with fed blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. beta-Cell hypertrophy was present at both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a global alteration in gene expression with decreased mRNA for insulin, IAPP, islet-associated transcription factors (pancreatic and duodenal homeobox-1, BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1 alpha), beta-cell metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps (Kir6.2, VDCC beta, and sarcoplasmic reticulum Ca(2+)-ATPase 3). Conversely, genes normally suppressed in beta-cells, such as lactate dehydrogenase-A, hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and Fas), and the transcription factor c-Myc, were markedly increased. In contrast, gene expression in low hyperglycemia rats was only minimally changed at 4 weeks but significantly changed at 14 weeks, indicating that even low levels of hyperglycemia induce beta-cell dedifferentiation over time. In addition, whereas 2 weeks of correction of hyperglycemia completely reverses the changes in gene expression of Px rats at 4 weeks, the changes at 14 weeks were only partially reversed, indicating that the phenotype becomes resistant to reversal in the long term. In conclusion, chronic hyperglycemia induces a progressive loss of beta-cell phenotype with decreased expression of beta-cell-associated genes and increased expression of normally suppressed genes, these changes being present with even minimal levels of hyperglycemia. Thus, both the severity and duration of hyperglycemia appear to contribute to the deterioration of the beta-cell phenotype found in diabetes.
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PMID:Critical reduction in beta-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes. 1243 14

For the application of microarray technology as an additional endpoint in toxicological studies, there is a need to understand associations between pathological processes and gene expression alterations. In the current study, we investigated gentamicin as a nephrotoxic model compound. Gene expression changes of the kidney in response to a dose of 80 mg/kg gentamicin were analyzed by using DNA microarray technology and alterations in gene expression were associated with results from conventional histopathological investigations and with the described pathomechanisms of gentamicin. Under the conditions of our experiment, the mRNA level of 211 genes were found to be deregulated by gentamicin. The gentamicin-induced affection of proximal convoluted tubules was associated with a strong up-regulation of mRNAs encoding for proteins which are used as nephrotoxicity markers in urine and plasma such as Kim-1, Osteopontin and TIMP1. Candidate marker genes for nephrotoxicity such as GATM were deregulated. Gentamicin-induced lysosomal phospholipidosis was indicated by deregulation of lysosomal located gene products such as ATP6V1D, a subunit of the lysosomal H+ transporting ATPase. Effects on glucose transport and metabolism were indicated by the down-regulation on SGLT-2 and glucose-6-phosphatase. Renal cell apoptosis was indicated by up-regulated genes as TP53 and BAX. The role of oxidative stress in gentamicin toxicity was reflected by deregulation of transferrin receptor and heme oxygenase. The results of the study show the potential of microarray technology to study a complex mechanism of toxicity in a single study.
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PMID:Identification of genes involved in gentamicin-induced nephrotoxicity in rats--a toxicogenomic investigation. 1966 12