UNIPROT:P17174 - FACTA Search

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Query: UNIPROT:P17174 (aspartate aminotransferase)
14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Cu concentration was about 40 and 60 times higher in the liver in Long-Evans with a cinnamon-like coat color (LEC) rats aged 80 days (without hepatitis) and 130 days (with hepatitis), respectively than in the liver in Fischer rats. Most hepatic Cu was recovered in the cytosol fraction. Furthermore, about 96% and 84% of the cytosolic Cu was found in the metallothionein region on a Sephadex G-75 column in LEC rats aged 80 and 130 days, respectively. The hepatic metallothionein concentration was about 130 to 140 times higher in LEC rats than in Fischer rats when the concentration was expressed as metallothionein-bound Cu. Three forms of Cu-metallothionein were isolated by DEAE-cartridge. Although the concentration of hepatic Cu-metallothionein and its composition of polymorphic form were not changed greatly in hepatitis phase (in the 130-day-old LEC rats), activities of serum enzymes, aspartate aminotransferase (GOT) and alanine aminotransferase (GPT) were increased significantly. The LEC rat showed a significantly low concentration of biliary Cu and markedly low activity of ceruloplasmin (as ferroxidase). Serum Cu showed a low concentration in the 80-day-old LEC rats, but recovered to the control level in the 130-day-old LEC rats. The abnormal accumulation of Cu may be due to the inherent reduction of excretion of Cu into the bile and blood. Such deposition may be a trigger for the onset of the spontaneous hepatitis occurring at 90-120 days after birth and for the onset of hepatoma later.
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PMID:Excessive accumulation of hepatic copper in LEC rats aged 80 days without hepatitis and 130 days with hepatitis. 144 42

Dose- and time-related effects of Cd (II) (0.5 or 1.0 mg/kg, Cd as CdCl2.H2O, subcutaneously, daily for 48 h, 1, 3, or 6 wk) were investigated in rats. A dose-related increase in the activity of plasma alkaline phosphatase (ALP), lactate dehydrogenase (LDH), aspartate aminotransferase (GOT), and alanine aminotransferase (GPT) was evident only at 6 wk, whereas an early rise in ALP and LDH was seen at 3 wk in 1.0 mg Cd group only. The hepatic and renal metallothionein (MT) induction displayed a dose- as well as time-related increase with Cd accumulation. A significant increase in hepatic Zn and renal Cu, no change in hepatic Cu, and a slight increase in renal Zn was observed. Urinary ALP and leucine aminopeptidase (LAP) showed an initial increase at 48 h, thereafter returned to near normal. A second phase of enzymuria (ALP, LAP, GOT, GPT, gamma-glutamyl transpeptidase), proteinuria, and aminoaciduria occurred at 6 wk in a dose-related manner. The urinary excretion of specific renal enzymes appeared closely related to the MT induction and organ Cd levels.
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PMID:Biochemical response to cadmium. Dose-time effect. 171 72

These studies were designed to determine if macular mutant mouse, which is a proposed animal model of Menkes' kinky-hair disease, is sensitive to the acute toxic effect of Cu as compared to normal and heterozygote mice. Single sc injection of Cu were administered to 6- to 8-day-old mice, and mortalities were recorded for 30 days. The copper treatment at high doses (12 to 25 mg Cu/kg) was very toxic to mutant mice as compared to normal mice, and almost all mutant mice died within 10 days after injection. The effect of Cu toxicity on heterozygote mice was intermediate. The LD50 values 3 days after injection of Cu were 29.5 mg Cu/kg for normal mice, 23.5 mg Cu/kg for heterozygote mice, and 15.5 mg Cu/kg for mutant mice. In Cu-injected mutant mice (11 and 18 mg Cu/kg), significant elevations in serum aspartate aminotransferase and lactate dehydrogenase activity occurred as compared to Cu-injected normal and heterozygote mice. However, no significant elevations in serum creatinine and urea nitrogen contents in Cu-injected mutant were observed as compared to normal and heterozygote mouse. No significant differences in hepatic metallothionein(MT) and MT-1 mRNA, and serum ceruloplasmin oxidase activity levels were observed between Cu-injected normal and mutant mouse. These results indicated that macular mutant mice was sensitive to the acute toxic or hepatotoxic effects of Cu as compared to normal and heterozygote mice.
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PMID:Copper-induced toxicity in macular mutant mouse: an animal model for Menkes' kinky-hair disease. 187 75

This study was concerned with the role of Cu and Cu-MT (metallothionein) in oxidative stress. Because hepatic Cu and Cu-MT concentrations are known to be high in the 3-day-old guinea pigs but decline to low adult levels by 7 days of life, the hepatotoxicity of ferric nitrilotriacetate (FeNTA) in the developing guinea pig was used as the experimental model in the present study. Results of this study showed that the hepatotoxic response to FeNTA (3.5 mg Fe /kg i.p.) as measured by elevation in serum aspartate aminotransferase activity, increase in lipid peroxidation, decrease in reduced glutathione/oxidized glutathione ratio and histopathological changes was higher in 3-day-old than in 7-day-old and adult guinea pigs. Furthermore, pretreatment of 7-day-old guinea pigs with cupric sulfate (0.5 mg Cu++/kg i.p.) increased hepatic Cu and Cu-MT levels and enhanced susceptibility to FeNTA. FeNTA treatment resulted in the oxidation of MT thiolates and reduction in the metal binding capacity and Cu content of MT in the 3-day-old and Cu-pretreated 7-day-old animals, providing evidence for the interaction between Cu-MT and cellular oxidants. In vitro study with FeNTA and hepatic microsomes revealed no age-related differences in microsomal lipid peroxidation; however, this parameter was stimulated in the presence of control or heat-treated cytosols isolated from 3-day-old but not those of 7-day-old animals. These observations were consistent with the involvement of Cu-MT, a heat-stable metalloprotein, in the sensitization of hepatic tissues to oxidative injury in the 3-day-old animal. Moreover, in vitro study involving the use of D-penicillamine, a Cu chelating agent, showed that the sensitization effect of Cu-MT was mediated by Cu ions. The results of this study suggest that Cu-MT may have a prooxidative property and tissues with high Cu-MT levels may be particularly susceptible to oxidative stress.
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PMID:Age-related differences in iron-nitrilotriacetate hepatotoxicity in the guinea pig: role of copper metallothionein. 189 Jun 21

The present investigation examines the possibility that Cd and ethanol have a significant toxicological interaction. This examination was warranted as exposure to either chemical is known to compromise human health. Inasmuch as both chemicals affect the morphology, biochemistry, and physiology of liver, it seemed reasonable to consider liver as a possible site of interaction. Specifically, the hypothesis that ethanol alters the hepatotoxic action of Cd was evaluated. Accordingly, male rats were injected iv with hepatotoxic (3.0 mg/kg) or lethal (4.5 mg/kg) dosages of Cd, 24 hr after single-dose ethanol administration (7 g/kg, po). Cd-induced hepatotoxicity was assessed by measuring the activities of alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase in serum collected 10 hr after Cd injection. Lethality was assessed by recording the number of survivors over a 7-day period. Prior exposure to ethanol substantially reduced the lethal and hepatotoxic properties of Cd. Two mechanisms were evaluated in an effort to explain ethanol-induced suppression of Cd hepatotoxicity. Ethanol pretreatment was postulated to: (1) enhance Cd excretion in bile thereby decreasing hepatic Cd content and/or (2) reduce the interaction between Cd and target sites in liver such as organelles and cytosolic high-molecular-weight (HMW) proteins. The first proposed mechanism was incorrect as the biliary excretion of Cd was nearly abolished and the concentration of Cd in whole liver increased (33%) as a result of ethanol exposure. The second proposed mechanism was a plausible explanation of ethanol-induced suppression of Cd hepatotoxicity because ethanol pretreatment decreased (approximately 60%) the content of Cd in nuclei, mitochondria, and endoplasmic reticulum, and nearly eliminated the association of Cd with cytosolic HMW proteins. Reduction in the concentration of Cd in potential target sites of intoxication was caused by a metallothionein-promoted sequestration of Cd in cytosol.
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PMID:Ethanol decreases cadmium hepatotoxicity in rats: possible role of hepatic metallothionein induction. 226 92

The effect of N-benzyl-D-glucamine dithiocarbamate (BGD) on the renal toxicity induced by acute exposure to cadmium-metallothionein (Cd-MT) in rats was studied. Rats were injected intraperitoneally with BGD (400 mumol/kg) 6, 12, or 24 h after intraperitoneal injection of Cd-MT (1.78 mumol Cd as Cd-MT/kg) and thereafter they received three injections of BGD (400 mumol/kg) daily for 3 days. Urinary protein concentration and aspartate aminotransferase (AST) activity significantly increased 1 day after Cd-MT treatment and decreased to control levels at 9 days after the treatment. Urinary excretion of glucose and amino acids rose gradually reaching maximum levels 5 days after Cd-MT treatment and returned to the control levels at 9 days. BGD injection significantly reduced the increases in the urinary excretion of protein, AST, glucose and amino acid, which were produced by Cd-MT treatment. Significant increases in urine volume were observed after Cd-MT treatment. BGD injection inhibited the increase in urine volume caused by Cd-MT treatment. A long time interval (12 and 24 h) between the administrations of Cd-MT and BGD resulted in a decreased protective effect of BGD against Cd-MT-induced renal damage. Following Cd-MT injection, the major route of excretion of cadmium (Cd) was via the urine and the kidney was the major site of accumulation of Cd. BGD injection remarkably increased the urinary excretion of Cd, resulting in a significant reduction in the kidney Cd concentration. The results of this study indicate that BGD injection is effective in decreasing the Cd concentration in the kidney, resulting in the protective effect on Cd-MT-induced renal damage.
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PMID:Effect of N-benzyl-D-glucamine dithiocarbamate on renal toxicity induced by cadmium-metallothionein in rats. 235 Feb 40

To study the influence of hepatic metallothionein (MT) on the hepatotoxic response to carbon tetrachloride (CCl4), adult male rats were pretreated with a 10 mg X kg-1 dose of zinc (Zn) 24 h prior to CCl4 (i.p., l mL X kg-1) treatment. Zn pretreatment increased the hepatic MT concentrations markedly and reduced the magnitudes of the CCl4-induced reduction of cytochrome P450 concentration as well as elevation of serum alanine aminotransferase and aspartate aminotransferase activities when determined at 4 or 24 h following CCl4 treatment. Treatment of Zn-exposed animals with CCl4 also resulted in significant reduction of the concentrations of hepatic MT (as determined by the cadmium-saturation method) as well as cytosolic Zn. Sephadex G-75 chromatographic study of hepatic cytosols showed that MT-bound Zn was selectively depleted by CCl4 exposure. Moreover, it was demonstrated that CCl4, after metabolic activation, reduced the cadmium binding capacity of Zn-induced hepatic MT in vitro. To examine the possible protective effect of Zn independent of induction of MT synthesis, CCl4 was administered 2 h following Zn pretreatment and the hepatotoxic response was examined 4 h later. This study revealed limited protection by Zn prior to the induction of MT synthesis. These data further support a role of MT in the modulation of CCl4 hepatotoxicity.
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PMID:Interaction of metallothionein and carbon tetrachloride on the protective effect of zinc on hepatotoxicity. 379 Oct 46

Rats were injected sc with 0.5 mg Cd/kg, 6 days/week, for up to 26 weeks. Hepatic and renal function and tissue Cd and metallothionein (MT) content were determined in tissues and plasma at various times after Cd injection. Cd in liver and kidney increased linearly for the first 10 weeks of treatment, but thereafter hepatic concentrations of Cd decreased by 33% whereas the content of Cd in kidney remained constant. MT in liver and kidney increased linearly during the first 12 weeks of Cd treatment to 4400 and 2300 micrograms MT/g, respectively, but rose only slightly thereafter. Circulating concentrations of MT progressively increased beginning 2 weeks after Cd treatment and were approximately 10 times control values in rats dosed with Cd for 12 or more weeks. Plasma activities of alanine and aspartate aminotransferase exhibited a time course similar to that observed with MT, and were elevated as early as the sixth week of Cd exposure. Sharp increases in activities of these enzymes also occurred after 10 to 12 weeks of dosing. Hepatic microsomal metabolism of benzo[a]pyrene and ethylmorphine was severely attenuated beginning 4 weeks after Cd. Renal injury occurred after hepatic damage, as evidenced by decreased in vitro p-aminohippuric acid uptake beginning 8 weeks after exposure. Urine outflow increased threefold 11 weeks after Cd exposure began, while urinary protein and Cd excretion increased beginning at Week 9. These data indicate the liver is a major target organ of chronic Cd poisoning, and suggest that Cd-induced hepatic injury, via release of Cd-MT, may play an important role in the nephrotoxicity observed in response to long-term exposure to Cd.
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PMID:Cadmium-induced hepatic and renal injury in chronically exposed rats: likely role of hepatic cadmium-metallothionein in nephrotoxicity. 397 9

Experiments were conducted to examine the role of zinc in the prevention of bromobenzene hepatoxicity in male rats. Bromobenzene (BB) (7.5 mmol/kg, ip) produced a marked hepatotoxicity as evidenced by increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and a marked depression in hepatic glutathione (GSH) content 24 hr after administration. The administration of zinc (92 mumol Zn/kg, ip, at 48 and 24 hr prior to the bromobenzene) ameliorated the bromobenzene elevations in plasma AST (25%) and plasma ALT (50%) but did not alter the decreases in hepatic GSH. Following administration of [14C]BB, the radioactive label was distributed primarily in the cytosolic and lipid fractions derived from liver homogenates. Furthermore, the subcellular distribution of [14C]BB was not altered by zinc pretreatment. The extent of covalent binding of [14C]BB metabolites to hepatic tissue was significantly depressed in zinc-treated rats. Zinc induced the hepatic levels of metallothionein but [14C]BB did not bind to this sulfhydryl rich protein. Further experiments showed that zinc treatment depressed cytochrome P-450 content, the activity of NADPH cytochrome c reductase, and the metabolism of aniline, but not that of ethylmorphine. These studies suggest that the hepatoprotective effect of zinc against bromobenzene toxicity does not involve altered binding of the reactive toxic metabolite to glutathione or metallothionein, but it may be mediated by the inhibitory effect of zinc on the microsomal cytochrome P-450-dependent drug metabolizing system.
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PMID:Amelioration of bromobenzene hepatotoxicity in the male rat by zinc. 398

Pretreatment with Mn2+ is known to produce tolerance to Cd2+-induced lethality. This study was designed to determine the mechanism of tolerance to Cd2+-induced lethality and hepatotoxicity following Mn2+ pretreatment. Rats given 36 mumoles Cd2+/kg, i.v., died within 10-20 hr while only one of nine rats pretreated with Mn2+ (250 mumoles/kg, s.c., 48 and 24 hr prior to Cd2+ challenge) died. Ten hours after Cd2+, plasma aspartate aminotransferase and sorbitol dehydrogenase activities were elevated markedly, and extensive histopathologic lesions of the liver were evident in control rats but not in Mn2+-pretreated rats. To examine the mechanism of this tolerance, distribution of Cd2+ to fourteen organs and the subcellular distribution in six organs were determined in control and Mn2+-pretreated rats. Two hours after challenge (31 mumoles Cd2+/kg, i.v., 0.75 microCi 109Cd2+/mumol Cd2+), the distribution of Cd2+ to liver markedly increased after Mn2+ pretreatment with concomitant decreases in other tissues. Mn2+ pretreatment also resulted in a marked difference in the hepatic subcellular distribution of Cd2+ with more present in cytosol and less associated with organelles. Gel-filtration chromatography indicated that most cytosolic Cd2+ was bound to a low molecular weight protein. Isolation and partial characterization of this protein suggest that it is identical to metallothionein (MT); it had a similar relative elution following gel-filtration chromatography, had low absorbance at 280 nm and, after separation into two isoproteins by DEAE A-25 anion exchange chromatography, had the same mobility after electrophoresis on non-denaturing polyacrylamide gels as Cd2+-induced metallothioneins. These data suggest that Mn2+ pretreatment reduces Cd2+-induced hepatotoxicity by altering the hepatic subcellular distribution of Cd2+ with more Cd2+ binding to MT in the cytosol. This decreased hepatotoxicity is probably responsible for tolerance to Cd2+-induced lethality.
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PMID:Mechanism of manganese-induced tolerance to cadmium lethality and hepatotoxicity. 399 53

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