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)

The aim of this study was to determine the influence of aging on diquat-induced redox cycling in liver microsomes and diquat hepatotoxicity in rats. Diquat-stimulated production of superoxide anion radical and NADPH-cytochrome c (P-450) reductase activity were measured in liver microsomes prepared from male Fischer 344 rats at ages representing young adulthood (5-6 months), middle age (15-16 months), and old age (24-27 months). Both activities were decreased substantially (40%) in old rats. Diquat-induced liver damage was assessed 6 hr after the administration of diquat (0.1 mmol/kg, ip) on the basis of serum ALT and sorbitol dehydrogenase activities, hepatic microsomal cytochrome P-450 loss, and histological evaluation. The classical manifestations of hepatotoxicity in diquat-treated rats were as severe in old rats as in young-adult ones, despite the age-associated drop in redox cycling capacity. Diquat treatment also resulted in decreased concentrations of hepatic glutathione and ascorbic acid, increased concentrations of hepatic nonheme iron, and decreased liver weights. The changes in glutathione, nonheme iron, and liver weight were more pronounced in livers of middle-aged and old rats than in those of young-adult rats. These age-dependent differences could not be explained on the basis of plasma diquat concentrations, which were similar in the three age groups of rats. The absence of an effect of aging on the hepatotoxic effects of diquat indicates that redox cycling capacity is not limiting for the development of liver damage. Other effects of diquat were influenced by aging, but their relevancy to the hepatotoxicity is uncertain.
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PMID:Redox cycling and hepatotoxicity of diquat in aging male Fischer 344 rats. 810 18

The concurrence of hypertension and hypercholesterolemia leads to the clinical need to lower lipids in hypertensive patients. Thus, it is interesting to evaluate the efficacy and safety of fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitor, in such a patient population. A retrospective analysis of the clinical efficacy and safety of fluvastatin was based on the data from 1815 patients who received fluvastatin at daily doses of > or = 20 mg compared with 783 patients taking placebo. The results showed that 332 (18.3%) of the fluvastatin-treated and 124 (15.8%) of the placebo-treated patients were identified as having hypertension. The percentage change from baseline of low-density lipoprotein cholesterol (LDL-C) in hypertensive patients taking fluvastatin at doses of 20 and 40 mg/day was -20% and -26%, respectively (placebo: 1.4%), and did not differ from the response in non-hypertensive patients. Increases in high-density lipoprotein cholesterol (HDL-C) as well as decreases in triglycerides with fluvastatin were not consistently different between hypertensive and non-hypertensive patients. Irrespective of the presence or absence of hypertension, confirmed (measured on two consecutive occasions) increases > three times the upper limit of normal in aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) were observed in three (0.2%) and 12 (0.7%) patients, respectively. With placebo, ALAT was increased in two patients (0.2%). The incidence of notable increases more than 10 times the upper limit of normal in creatine kinase was similar with fluvastatin compared with placebo (0.3% in both).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Efficacy and safety of fluvastatin in hypertensive patients. An analysis of a clinical trial database. 829 42

Fluvastatin, a new synthetic inhibitor of HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, has been studied in several models to examine its effects when used in combination with other lipid-modifying agents such as derivatives of fibric acid (bezafibrate), resins (cholestyramine), and niacin. The combination of fluvastatin with bezafibrate has been studied in a double-blind trial involving patients with well-documented familial hypercholesterolaemia. Fluvastatin 40 mg/day, combined with either bezafibrate 400 mg/day or cholestyramine 8 g/day, resulted in reductions in levels of low-density lipoprotein cholesterol (LDL-C), these being indistinguishable between the groups; however, significantly greater increases in levels of high-density lipoprotein cholesterol (21.3%) and reductions in levels of triglycerides (25.1%) were seen with the fluvastatin-bezafibrate combination. No notable increases were seen in levels of serum creatine kinase, aspartate aminotransferase, or alanine aminotransferase, and no cases of myopathy were observed. In a study model that examined low-dose combinations of fluvastatin with cholestyramine, reductions in levels of LDL-C of 15.8% and 19.3% were seen with fluvastatin 10 mg and 20 mg, respectively. After an 8-week interval in which a daily dosage of cholestyramine 8 g was added, from baseline, reductions of 26.3% in the 10 mg fluvastatin-cholestyramine group and 31.2% in the 20 mg fluvastatin-cholestyramine group were observed, whereas the placebo-cholestyramine group displayed a reduction of 14.9%. Doubling the resin dosage to 16 g/day for the final 8 weeks of the study provided little additional benefit. Myotoxicity has been observed when lovastatin is coadministered with niacin, and so the combination of niacin with fluvastatin has also been studied to examine the possibility of this effect occurring. Patients were randomised to either fluvastatin 20 mg or placebo for 6 weeks, after which time open-label niacin was administered to all patients and titrated to a final dosage of 3 g/day. After 6 weeks, fluvastatin produced a 20.8% reduction in LDL-C levels from baseline. When combined with niacin, a 43.7% reduction was noted at the week 15 endpoint, against the 26.5% reduction seen with niacin monotherapy. The combination was well tolerated, with no reports of myopathy or of significant elevations in creatine kinase or liver transaminase levels. Combinations of fluvastatin with a variety of other agents have been shown to have significant effects on lipid profiles, with no evidence to date of clinically remarkable safety findings. Thus, the use of combination therapies may result in optimal management of patients with moderately severe hypercholesterolaemia and mixed dyslipidaemic profiles.
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PMID:Fluvastatin in combination with other lipid-lowering agents. 1949 70

We found that NADPH-dependent ubiquinone reductase (NADPH-UQ reductase) in rat liver cytosol reduces ubiquinone (UQ) to ubiquinol (UQH2) in lipid membranes and consequently inhibits lipid peroxidation [Takahashi T., et al., Biochem. J., 309, 883-890 (1995)]. Here we examined whether or not this UQH2-regenerating system functions as a cellular antioxidant defense in animals. Rats were given UQ-10 for 2 weeks, and were then exposed to carbon tetrachloride (CCl4). The UQ-10 supplement increased only in the NADPH-UQ reductase and the UQH2-10 pool of rat liver without any appreciable change in the levels of other antioxidant factors. On the other hand, CCl4 markedly increased plasma aspartate aminotransferase and alanine aminotransferase, liver weight and thiobarbituric acid reacting substances formation, which are indicators of CCl4-hepatitis, and it decreased the liver levels of L-ascorbic acid, reduced form of glutathione (GSH), alpha-tocopherol, NADPH-UQ reductase and glutathione S-transferase. However, all the above indicators of CCl4-induced hepatitis were significantly improved in rats given UQ-10. Furthermore, alpha-tocopherol, but neither L-ascorbic acid nor GSH, was significantly saved. UQ-10 supplement also was recovered glutathione S-transferase and NADPH-UQ reductase activities slightly. These results indicated that UQ-10 given to rats increased the cellular UQH2-10 pool and cytosolic NADPH-UQ reductase activity in their livers, resulting in the inhibition of lipid peroxidation in the biomembranes, and consequently protected the rats from the CCl4-hepatotoxicity.
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PMID:Cellular antioxidant defense by a ubiquinol-regenerating system coupled with cytosolic NADPH-dependent ubiquinone reductase: protective effect against carbon tetrachloride-induced hepatotoxicity in the rat. 887 5

The objective of this open trial was to investigate the efficacy and safety of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin in hypercholesterolemic patients already receiving probucol. All of the participants had hypercholesterolemia. i.e. serum total cholesterol > or = 220 mg/dl, despite administration of probucol, 500 mg/day, for more than 4 weeks. After this, fluvastatin, 30 mg/day, was added to probucol treatment for 12 weeks. Twenty-seven patients were recruited into this study; all were evaluated for safety, and 22 were evaluated for efficacy. The addition of fluvastatin to the probucol regimen produced a significant further reduction in serum total and low-density lipoprotein cholesterol concentrations (of 18 and 20%, respectively; p < 0.001); these effects were fully established within 4 weeks of treatment and were maintained throughout the treatment. Fluvastatin did not affect the serum high-density lipoprotein cholesterol concentration. Fluvastatin treatment decreased serum triglyceride concentrations slightly in all patients (not significant); in patients with hypertriglyceridemia, triglyceride levels were decreased significantly by 34% (p < 0.01; serum triglycerides > or = 150 mg/dl). In addition, fluvastatin significantly decreased serum apolipoprotein B, C-II, C-III and E levels, whereas serum apolipoprotein A-I and A-II levels were unaffected. One patient complained of slight abdominal discomfort during fluvastatin administration, but relationship to fluvastatin remains unclear. One patient had slight elevation of the serum alanine aminotransferase level, and another patient had an elevated gamma-glutamyl transferase level. The addition of fluvastatin to probucol treatment can be considered to be an effective and well tolerated treatment in hypercholesterolemic patients.
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PMID:Efficacy and safety of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin in hyperlipidemic patients treated with probucol. 909 17

To assess the long-term efficacy and use of fenofibrate together with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin") in the treatment of elevated levels of triglycerides and low-density lipoprotein (LDL) cholesterol, we conducted a study that compared a before- and after-case series. The study involved 80 patients with a diagnosis of combined hyperlipidemia and existing coronary artery disease (81% of patients) or outpatients with > or = 3 risk factors for coronary artery disease who had been receiving treatment at a tertiary care center. Fasting biochemical measures were obtained at baseline during monotherapy with a statin consisting of pravastatin 20 mg once daily or simvastatin 10 mg once daily (39 patients) or fenofibrate 300 mg once daily (41 patients), and during a 2-year period of combination therapy. This combination therapy comprised fenofibrate 300 mg once daily or micronized fenofibrate 200 mg once daily taken together with pravastatin 20 mg once daily (63 patients) or simvastatin 10 mg once daily (17 patients). The main outcome measures were: (1) absolute and percent change in total cholesterol, triglycerides, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol; (2) percentage of patients with alanine aminotransferase > or = 2x the upper limits of normal on any occasion; (3) percentage of patients with creatinine kinase > or = 3 times the upper limits of normal on any occasion; (4) absolute changes in alanine aminotransferase and creatinine phosphokinase; and (5) months on combination therapy. Patients receiving combination therapy had a mean total cholesterol (+/- standard error of the mean [SEM]) that was significantly decreased by 26+/-1%, triglycerides by 41+/-3%, and LDL cholesterol by 28+/-2%, and mean HDL cholesterol that was significantly increased by 22+/-6%. These changes correspond to mean absolute changes of total cholesterol: -75+/-5 mg/dL; triglycerides: -94+/-13 mg/dL; LDL cholesterol: -52+/-5 mg/dL; and HDL cholesterol: 5+/-1 mg/dL. During combination treatment, alanine aminotransferase increased by 2+/-2 U/liter (not significant) and creatinine phosphokinase decreased by 4+/-13 U/liter (not significant). During treatment, 8 patients (10%) had transitory isolated elevations in alanine aminotransferase levels > or = 2 times the upper limits of normal and 2 patients (2.5%) had an isolated and transitory elevation of creatinine kinase (> or = 3x but < 6x upper limits of normal) without associated muscle symptoms. Patient-years on combination therapy equaled 220.6 (average 2.06 years per patient). The results demonstrated that combination treatment with fenofibrate and low-dose simvastatin or pravastatin is generally safe and effective for the treatment of combined hyperlipidemia in patients with normal hepatic and renal function.
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PMID:Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. 952 16

3-Methylcholanthrene, an inducer of P448-type cytochromes (mostly 1A1 and 1A2), and phenobarbital, an inducer of P450-type cytochromes (mostly 2B1 and 2B2), are prototypical for the actions of many xenobiotics. They cause endocrine disruption by affecting, among others, steroid hormone levels. Rats were treated with single bolus doses of 3-methylcholanthrene or phenobarbital, and enzyme activities that are controlled by glucocorticoids were measured in liver and kidney. The activities of the cytosolic enzymes L-alanine aminotransferase, indoleamine 2,3-dioxygenase (L-tryptophan pyrrolase), phosphoenolpyruvate carboxykinase, L-serine dehydratase and L-tyrosine aminotransferase were affected in a similar fashion: an initial activity reduction followed by two overshoots of activity 1 and 2 days after dosing. 3-Hydroxy-3-methylglutaryl coenzyme A reductase, the microsomal key enzyme of sterol synthesis, responded with a temporary reduction of activity only and evidently lost its diurnal rhythm. The time course of these changes is most likely caused by a combination of sub-physiological levels of glucocorticoids plus changes of other regulatory hormones elicited by feed intake, postprandial state, etc. A possible role for a combined action of the arylhydrocarbon (Ah) and glucocorticoid receptors in the effects of 3-methylcholanthrene is also suggested.
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PMID:The enzyme inducers 3-methylcholanthrene and phenobarbital affect the activities of glucocorticoid hormone-regulated enzymes in rat liver and kidney. 962 May 44

Effects of a single dose of betaine on the chloroform-induced hepatotoxicity were examined in adult male ICR mice. Administration of betaine (1000 mg/kg, ip) 1 to 7 hr prior to a chloroform challenge (0.25 ml/kg, ip) resulted in remarkable enhancement of hepatotoxicity as indicated by increases in serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. The potentiation of hepatotoxicity was most significant when mice were treated with betaine 4 hr earlier than chloroform. However, a 24 hr prior administration of betaine protected the animals from induction of the chloroform hepatotoxicity. Thus, its effect appeared to be highly dependent on the time lapse from the betaine pretreatment to the challenge of mice with chloroform. Betaine treated either 4 or 24 hr prior to sacrifice did not alter the hepatic contents of cytochrome P-450, cytochrome b5, or NADPH cytochrome P-450 reductase activity. Accordingly the hepatic microsomal p-nitroanisole O-demethylase, aminopyrine N-demethylase, or p-nitrophenol hydroxylase activities were not influenced by the betaine pretreatment. Betaine was shown not to affect any of the enzyme activities associated with glutathione (GSH) conjugation reaction, such as glutathione S-transferases (GSTs), glutathione disulfide (GSSG) reductase and GSH peroxidase irrespective of the time of its administration. When betaine was administered to mice 2-6 hr prior to sacrifice, hepatic GSH level, but not plasma GSH, was decreased significantly. Enhancement of the chloroform hepatotoxicity by betaine correlated well with the reduction in hepatic GSH levels. Both hepatic and plasma GSH levels were elevated in mice 24 hr following the betaine treatment. The results suggest that betaine affects induction of the chloroform hepatotoxicity by modulating the availability of hepatic GSH, which appears to be associated with its role in the transsulfuration pathway in the liver.
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PMID:Effects of singly administered betaine on hepatotoxicity of chloroform in mice. 973 16

This study investigated the potential alteration in the amount of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase messenger RNA (mRNA) and lipoprotein lipase (LPL) mRNA in the livers of C57BL/6 mice after long-term (200 days) treatment with the nonionic surfactant called poloxamer 407 (P-407). Previously, P-407 has been used to produce a dose-controlled hyperlipidemic state in C57BL/6 mice with subsequent formation of atherosclerotic lesions. Five groups of mice were studied; controls (C); mice fed a standard chow diet enriched with only cholic acid (CH); mice fed the high-cholesterol, high-fat Paigen diet (HF); mice treated with 0.5 g/kg P-407 every third day (P); and mice administered 0.5 g/kg P-407 every third day while consuming a diet identical to that of mice in group CH (PC). Neither a significant (p < 0.05) weight loss nor alteration in liver enzymes (AST and ALT) were observed for any group throughout the study when compared with the control mice. Total plasma cholesterol (CHOL) was significantly elevated compared with controls for mice in groups HF, P, and PC, whereas total plasma triglycerides (TG) were significantly increased for mice in only groups P and PC. Long-term ingestion of a high-fat diet or a diet enriched in cholic acid resulted in a significant (p < 0.05) reduction in HDL-CHOL when compared with controls. Plasma samples assayed at 200 days for mice in groups HF and P showed a shift in the lipoprotein fraction distribution primarily to VLDL-CHOL as compared with mice in group C in which, as expected, most of the CHOL was contained in the HDL fraction. The biologic activity of HMG-CoA reductase assayed in hepatic microsomal homogenates was significantly reduced for mice in groups CH (p < 0.01), HF (p < 0.01), and PC (p < 0.05), but not for mice in group P, when compared with control. A statistical analysis of the data demonstrated significant (p < 0.05) reductions in the HMG-CoA reductase mRNA levels in hepatic tissue for all treatment groups relative to mRNA levels determined for mice in group C. In contrast, no treatment group demonstrated a significant difference in hepatic LPL mRNA levels when compared with mRNA levels determined for control animals. These data demonstrate that P-407 administration to C57BL/6 mice significantly decreased the amount of HMG-CoA reductase mRNA detected in liver.
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PMID:Potential downregulation of HMG-CoA reductase after prolonged administration of P-407 in C57BL/6 mice. 1059 27

Solanum alatum Moench. has been shown to have a protective effect against carbon tetrachloride (CCl4)-induced liver injury. Solanum alatum treatment (100 mg/kg, p.o.) decreased the elevation of serum alanine aminotransferase (ALT; GPT) and aspartate aminotransferase (AST; GOT) induced by acetaminophen (paracetamol) (600 mg/kg, i.p.) administration. It also decreased the extent of visible necrosis in liver tissue. In addition, Solanum alatum treatment restored hepatic glutathione (GSH) depletion induced by acetaminophen (600 mg/kg, i.p.) administration. Microsomal enzyme levels such as P-450, reductase, and aniline hydroxylation enzyme were also restored to normal levels after Solanum alatum administration. The hepatoprotective mechanism may function through direct binding with acetaminophen toxic metabolites, decreasing the attraction of acetaminophen metabolites for other cellular GSH or thiol protein. Additionally, Solanum alatum treatment increased the concentration of hepatic GSH and maintained a high level activity of GSTase, which led to acceleration of the excretion of toxic acetaminophen metabolites.
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PMID:The hepatoprotective effects of Solanum alatum Moench. on acetaminophen-induced hepatotoxicity in mice. 1079 22


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