Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of either 2,5-dichloro-3-(glutathion-S-yl)-1, 4-benzoquinone (DC-[GSyl]BQ) or 2,5,6-trichloro-3-(glutathion-S-yl)-1,4-benzoquinone (TC-[GSyl]BQ) to male Sprague-Dawley rats caused dose-dependent (50-200 mumol/kg; iv) renal proximal tubular necrosis, as evidenced by elevations in blood urea nitrogen (BUN), and in the urinary excretion of lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (gamma-GT) and glucose. Renal proximal tubular necrosis was also confirmed by histological examination of kidney slices prepared from DC-(GSyl)BQ- and TC-(GSyl)BQ-treated animals. Administration of the corresponding hydroquinone conjugates (DC-[GSyl]HQ and TC-[GSyl]HQ), prepared by reducing the quinones with a threefold molar excess of ascorbic acid, resulted in a substantial increase in nephrotoxicity. Moreover, in contrast to other glutathione (GSH)-conjugated hydroquinones, the nephrotoxicity of both DC-(GSyl)HQ and TC-(GSyl)HQ was potentiated when rats were pretreated with AT-125, an irreversible inhibitor of gamma-GT. Neither the quinone-GSH nor the hydroquinone-GSH conjugates caused any effect on liver histology or serum glutamate-pyruvate transaminase levels. The results suggest that coadministration of ascorbic acid with DC-(GSyl)BQ or TC-(GSyl)BQ decreases their interactions with extrarenal nucleophiles, including plasma proteins, and thus increases the concentration of the conjugates delivered to the kidney, and hence toxicity. Furthermore the ability of AT-125 to potentiate the nephrotoxicity of DC-(GSyl)HQ and TC-(GSyl)HQ suggests that metabolism of these conjugates by gamma-GT constitutes a detoxication reaction.
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PMID:Inhibition of gamma-glutamyl transpeptidase potentiates the nephrotoxicity of glutathione-conjugated chlorohydroquinones. 167 58

In the present investigation, administration of a single i.p. dose of the anticancer drug merbarone [5-(N-phenylcarboxamido)-2-thiobarbituric acid] produced an acute and reversible decrease in renal function in female but not male Fischer 344 rats. The renal lesion in female rats was biochemically characterized as a decrease in p-aminohippuric acid accumulation by renal slices along with polyuria, glucosuria, proteinuria, and enzymuria. These functional changes were accompanied by histopathologic changes of focal tubular necrosis that was confined to the deep cortex and outer stripe of the outer medulla. The changes in these parameters were dose-dependent and were observed at doses as low as 0.2 x MELD(10) (12 mg/kg). This low merbarone dose increased urinary glucose and protein excretion by 26- and 9-fold, respectively, in the initial 16-h urine collection in female rats. This increase was accompanied by a 2- to 15-fold increase in the excretion of N-acetyl-beta-D-glucosaminidase (NAG), gamma-glutamyl transpeptidase (gamma-GTP), and lactate dehydrogenase (LDH) activities. No significant changes in renal function were observed in male rats apart from mild enzymuria after a high dose of merbarone (36 mg/kg). The drug did not increase urea nitrogen levels in male or female rats, reflecting the focal nature of this tubular lesion. Merbarone produced small elevations in serum transaminase activities [i.e., glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT)] at doses that produced marked alterations in renal function in female rats, suggesting only mild hepatotoxicity. The present study establishes the kidney as a possible dose-limiting target organ for merbarone toxicity.
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PMID:Nephrotoxicity of 5-(N-phenylcarboxamido)-2-thiobarbituric acid in the Fischer 344 rat. 259 97

Lovastatin, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase, has been shown to be highly effective in lowering serum cholesterol in animals and humans and thus represents a promising approach to the treatment and prevention of cardiovascular disease. During the preclinical safety assessment of lovastatin, oral doses that were tolerated by dogs, rats and mice were found to be lethal to rabbits in subacute studies. Postmortem findings in rabbits consisted of centrilobular hepatic necrosis, frequently accompanied by renal tubular necrosis and occasionally gallbladder necrosis. The liver lesions were associated with up to 300-fold elevations in serum aspartate and alanine aminotransferase activities, whereas the kidney lesions resulted in accumulations of serum urea nitrogen and creatinine. The organ damage was preceded by a progressive decline in food consumption and loss of body weight. All histopathological and serum biochemical changes induced by lovastatin were completely prevented by coadministration of mevalonate, the product of the inhibited HMG-CoA reductase enzyme. In addition, administration of mevalonate after the onset of lovastatin-induced hepatotoxicity effectively reversed the toxicity despite continued drug treatment. These findings indicated that the toxicity of high doses of lovastatin to rabbits is a consequence of a highly exaggerated pharmacologic action in blocking mevalonate synthesis. However, supplementation of lovastatin-treated rabbits with oral doses of the major product of mevalonate metabolism, cholesterol, paradoxically enhanced the liver and kidney damage, which suggested that the toxicity of lovastatin stemmed from depletion of a nonsterol metabolite(s) of mevalonate critical for cell viability.
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PMID:Toxicity of the HMG-coenzyme A reductase inhibitor, lovastatin, to rabbits. 291 66

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to Mongolian gerbils by ip injection was 2.0 (2.26-1.77) mg/kg body weight. The gross alterations observed at autopsy were pallor and mottling of the kidneys and liver and congestion of the spleen. The histopathological alterations seen were renal tubular degeneration and necrosis, degenerative changes in hepatocytes, and congestion of the spleen. The morphopathogenesis of lesions after a single ip LD50 dose was evaluated in a second study. The histopathological alterations that were observed were focal degeneration and necrosis of hepatocytes and renal tubular degeneration and necrosis. Hepatic lesions were observed in gerbils killed between 2 and 12 hr after dosing and included multifocal cytoplasmic vacuolation and coagulative necrosis of hepatocytes. The renal lesions were first observed 2 hr after dosing and increased to maximum severity at 40 hr after dosing. Tubular regeneration accompanied ongoing tubular necrosis at the end of the test period. The activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were increased 4 hr after dosing, peaked at 24 hr and remained elevated to the end of the test period. Serum K+ concentration was increased 16 hr after dosing and remained elevated to the end of the test period. In a third study, rubratoxin B was administered ip once daily for 7 days at doses of 25, 50 or 75% of the ip LD50. Toxicity was dose related and cumulative with multiple doses. Histopathological alterations included renal tubular degeneration and necrosis, mild tubular dilation and focal necrosis of hepatocytes. In a fourth study, rubratoxin B was administered ip at a dose of 25% of the ip LD50 once daily for 7 days. Histopathological alterations included renal tubular degeneration, mild renal tubular dilation and focal necrosis of hepatocytes. Activities of AST and ALT in serum were slightly increased after multiple doses of rubratoxin B. Results of urinalysis indicated hepatic and renal tubular damage.
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PMID:Rubratoxin B mycotoxicosis in the Mongolian gerbil. 296 71

In the first test, aluminum nitrilotriacetate (Al-NTA), aluminum chloride, aluminum potassium sulfate, or saline was injected ip, employing male Wistar rats. Each group consisted of ten rats. Al was given in a dose of 5 mg Al/kg body wt/day, for 14 days. Only those rats given Al-NTA showed morphological damage of the liver and kidney. Damages included diffuse midzonal coagulation necrosis of hepatocytes and acute proximal tubular necrosis of the kidney at Day 4. Seven of ten rats given Al-NTA died within 5 days. The second test was performed in metabolic cages. Al-NTA, in a dose of 1.5 to 2.0 mg Al/kg body wt/day, and NTA, of an equivalent dose, were injected ip for 54 days. Midzonal coagulation necrosis and some regenerative changes were observed in the hepatic parenchyma at Day 8. At the end of the study, complete regeneration occurred in the liver. Biochemical tests at Days 6, 13, and 28 showed high amounts of GOT, GPT, LDH, gamma-GTP, and ALP. Necrosis of proximal tubular cells of the kidney and some regeneration was noted at Day 8. Metabolic acidosis was demonstrated at Days 6, 13, and 28. Moreover, from Day 38 on, atrophy of the nerve cells of the cerebrum and demyelination of the brain stem were observed. Control rats given NTA did not exhibit any organ damage. It is concluded that a relatively small dose of Al can produce toxicosis when given with certain metal chelators.
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PMID:Liver, kidney, and central nervous system toxicity of aluminum given intraperitoneally to rats: a multiple-dose subchronic study using aluminum nitrilotriacetate. 643 9

Bromobenzene, at doses greater than 5.7 mmol/kg, produced renal proximal tubular necrosis and renal functional changes in mice. p-Bromophenol and o-bromophenol were the major urinary phenolic bromobenzene metabolites although m-bromophenol and 4-bromocatechol were also excreted in detectable quantities. With the exception of o-bromophenol, urinary metabolites were excreted primarily as conjugates. 4-Bromocatechol and the 3 bromophenol isomers were nephrotoxicants (measured as increased blood urea nitrogen and decreased accumulation of organic anions by renal cortical slices) but not hepatotoxicants (measured as serum glutamic pyruvate transaminase) in vivo at 0.56 mmol/kg (i.v.). Preincubation of renal cortical slices with each of these bromobenzene metabolites for 90 min resulted in dose-dependent decreases in the accumulation of p-aminohippurate and tetraethylammonium. At 10 mumol/preincubation (2.4 mM), organic ion accumulation was decreased maximally by all bromobenzene metabolites examined while equimolar amounts of bromobenzene were without effect. 4-Bromocatechol was the most potent nephrotoxicant in vitro. Administration of 0.53-2.12 mmol/kg (i.v.) 4-bromocatechol to mice resulted in a dose-dependent decrease in renal function while hepatic function was altered only slightly at the higher doses. The renal cortical necrosis produced by in vivo administration of 4-bromocatechol could not be distinguished histologically from that induced by bromobenzene. These results demonstrate that 4-bromocatechol and the 3 bromophenol isomers are nephrotoxicants that can be generated from bromobenzene in mice.
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PMID:Nephrotoxicity of phenolic bromobenzene metabolites in the mouse. 671 May 48

Subacute toxicity study of fenvalerate was carried out in broiler chicks after oral administration @ 525.6 mg/kg once daily for 28 days. The blood concentration of fenvalerate following 1 day post-administration (pd) was 39.65 +/- 2.67 micrograms/ml and maintained plateau thereafter up to day 21 pd, and then declined (18.46 +/- 1.47 micrograms/ml) on day 28 pd. Intestine contained maximum residue (7.46 +/- 1.96 micrograms/g) followed by fat (5.95 +/- 1.16 micrograms/g), brain (5.06 +/- 0.96 micrograms/g), liver (3.93 +/- 0.51 micrograms/g), kidney (3.79 +/- 0.72 micrograms/g) and heart (1.72 +/- 0.35 micrograms/g). Histopathological examinations showed focal areas of necrosis in liver, proliferation and fibrosis of bile duct, larger size of glomeruli, glomerular and tubular necrosis in treated birds. Fenvalerate significantly increased the cholesterol level in brain, GPT activity in liver and heart, GOT activity in heart, and alkaline phosphatase activity in heart and brain tissue. It significantly decreased the glycogen content in liver and heart, GOT activity in brain and acid phosphatase activity in all the tissues analyzed. It appears that comparatively fowl is resistant to fenvalerate toxicity.
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PMID:Subacute toxicity of fenvalerate in broiler chicks: concentration, cytotoxicity and biochemical profiles. 782 86

Rats were injected with gentamicin at doses of 20, 40 and 80 mg/kg per day for 6 consecutive days. The treatment caused nephrotoxicity as evidenced by dose-related increases in serum creatinine concentration and renal tubular necrosis. The nephrotoxicity was accompanied by reduced renal cortical and fasting blood glucose levels, and by increases in serum lactate concentrations. The activities of cortical malate dehydrogenase and alanine transaminase were significantly reduced by the three doses of gentamicin. On the other hand, aspartate transaminase activity was lowered only by the highest dose of antibiotic used. However, the activity of cortical glucose-6-phosphate dehydrogenase was altered by the 20 and 40 mg/kg doses of gentamicin, but not by the 80 mg/kg dose. The two lower doses reduced the lactate content of the cortex but activated lactate dehydrogenase. The activity of isocitrate dehydrogenase was not altered by any of the gentamicin doses used.
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PMID:Effect of gentamicin-induced nephrotoxicity on some carbohydrate metabolic pathways in the rat renal cortex. 785 4

Halogenated anilines and aminophenols are nephrotoxicants and hepatotoxicants in mammals. The purpose of this study was to determine the in vivo and in vitro nephrotoxic and hepatotoxic potential of 4-amino-2,6-dichlorophenol, a putative metabolite of 3,5-dichloroaniline. In the in vivo experiments, male Fischer 344 rats (four/group) were administered a single intraperitoneal (i.p.) injection of 4-amino-2,6-dichlorophenol (0.25, 0.38 or 0.50 mmol/kg) or vehicle (dimethylsulfoxide (DMSO), 1.0 ml/kg) and renal and hepatic function monitored for 48 h. Only minor changes in function or morphology were observed in the 0.25 mmol/kg treatment group. However, in the 0.38 mmol/kg treatment group evidence of both nephrotoxicity and hepatotoxicity were evident. Nephrotoxicity was characterized by increased proteinuria, glucosuria, hematuria, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased p-aminohippurate (PAH) accumulation and proximal tubular necrosis in the corticomedullary region of the kidney. Hepatotoxicity was characterized by elevated plasma alanine aminotransferase (ALT/GPT) activity and liver weight. Animals administered the 0.5 mmol/kg dose died within 24 h. In the in vitro experiments, the effect of 4-amino-2,6-dichlorophenol on organic ion accumulation, gluconeogenesis and lactate dehydrogenase (LDH) leakage was quantitated in liver and/or renal cortical slices. Organic anion accumulation was inhibited in renal cortical slices by 4-amino-2,6-dichlorophenol bath concentrations of 5 x 10(-6) M or higher, while organic cation uptake was decreased at 4-amino-2,6-dichlorophenol bath concentrations of 1 x 10(-5) M or greater. Renal and hepatic pyruvate-stimulated gluconeogenesis were inhibited and renal LDH leakage increased at 4-amino-2,6-dichlorophenol bath concentrations of 5 x 10(-5) M or greater. Increased LDH leakage from liver slices was not observed. These results demonstrate that 4-amino-2,6-dichlorophenol is a nephrotoxicant and hepatotoxicant in vivo and in vitro and that the kidney is more susceptible to 4-amino-2,6-dichlorophenol toxicity than the liver.
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PMID:In vivo and in vitro 4-amino-2,6-dichlorophenol nephrotoxicity and hepatotoxicity in the Fischer 344 rat. 802 37

In mice depleted of GSH by treatment with buthionine sulfoximine (BSO), thiabendazole (TBZ) causes renal injury characterized by an increase in serum urea nitrogen (SUN) concentration and by tubular necrosis. Previous studies have shown that TBZ requires metabolic activation before it produces nephrotoxicity and that the structure contributing to the toxicity of TBZ is the thiazole moiety of the molecule. TBZ and its thiazole analogues were examined for the ability to increase SUN concentration and serum alanine aminotransferase activity in GSH-depleted mice. Unsubstituted thiazole and thiazoles with 4- and/or 5-, and no 2-, substituents caused marked increases in SUN concentration, suggesting nephrotoxicity. Furthermore, the nephrotoxic potency of these thiazoles decreased with the increasing number and bulk of the 4- and/or 5-substituents. On the other hand, the target organ (the kidney or liver) and the toxic potency of 4-methylthiazoles were markedly altered with the type of substituents at the 2-position. These observations and the known toxicity of thiono-sulfur compounds led us to the hypothesis that the nephrotoxic thiazoles, which lack 2-substituents, would undergo microsomal epoxidation of the C-4,5 double bond and, after being hydrolyzed, the resulting epoxide would then be decomposed to form thioformamide, a possibly toxic metabolite. Evidence for this hypothesis was provided by the results that thioformamide and tert-butylglyoxal as the accompanying fragment were identified as urinary metabolites in mice dosed with 4-tert-butylthiazole and that thioformamide caused a marked increase in SUN concentration when administered to mice in combination with BSO.
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PMID:Possible role of thioformamide as a proximate toxicant in the nephrotoxicity of thiabendazole and related thiazoles in glutathione-depleted mice: structure-toxicity and metabolic studies. 847 8


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