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)

In clinical trials, all lipid-lowering agents have been associated with mild, asymptomatic elevations of alanine aminotransferase (ALT) and asparate aminotransferase enzymes. This, along with the fact that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are hepatotoxic in some animals, led the US Food and Drug Administration (FDA) to recommend monitoring of liver enzymes for all lipid-lowering agents, except the bile acid sequestrants. Because the drugs act by different mechanisms, ALT elevations may be a pharmacodynamic effect related to lipid lowering, rather than a direct effect of the drug. Animal studies support this assumption. ALT elevations of 3 times the upper limit of normal occur in <3% of patients in clinical trials of lipid-lowering drugs. The elevations are transient and often dose-related, and they usually revert to normal while continuing therapy and have never been associated with hepatotoxicity. Confounding factors include alcohol, acetaminophen, and pre-existing liver disease, such as chronic hepatitis C and type II diabetes with fatty liver, which are both associated with mild, intermittent elevations of ALT. The more important issue is whether or not lipid-lowering agents are hepatotoxic. There are case reports of hepatotoxicity (cholestasis, jaundice, hepatitis, chronic active hepatitis, fatty liver, cirrhosis and acute liver failure) with all of the drugs, except cholestyramine. To date there are just 5 cases of documented liver failure linked to lovastatin. There is no evidence that monitoring reduces the rate of hepatotoxicity. Mild elevations of ALT that occur with many drugs, including HMG-CoA reductase inhibitors, do not predict hepatotoxicity. Liver enzyme elevations appear to be a class characteristic of lipid-lowering agents. Hepatotoxicity is a rare idiosyncratic reaction, occurring only with sustained released nicotinic acid.
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PMID:Defining patient risks from expanded preventive therapies. 1085 89

The purpose of this study is to evaluate the acute and chronic toxicology of oral intake of fish oil (omega-3 fatty acid) and garlic combination food supplements. These supplements were proven to have beneficial effects on the lipid profile. Therefore, it is important to evaluate the potential long-term effects of fish oil and garlic combination supplements on the biochemistry of organ structure and function. The hypothesis to be tested was that acute and chronic high-dose supplements of fish oil and garlic may not adversely affect organ histology but may influence certain metabolic activities. A double-blind, placebo-controlled study was carried out using 28 Sprague Dawley rats separated into a placebo group (16 rats) and a supplement group (12 rats). The supplement group received the ingredients in chow inserts at a dosage that was equivalent to three times the maximum safe daily dosage for fish oil and the usual daily dosage for garlic (the maximum safe daily dosage recommended by the United States Food And Drug Administration for a 70-kg human is a total of 3 g/day intake of EPA and HDA omega-3 fatty acids from conventional and dietary sources. The usual daily garlic usage is garlic powder = 1200 mg). The study was conducted over a period of 12 months with evaluations performed at baseline, 2 months, 6 months, and 12 months. Results confirm the expected acute triglyceride, total cholesterol and LDL suppression at these higher dosages in the supplement group. Acutely and chronically, there were no differences in external appearance, level of activity, daily food consumption, blood cell count, kidney function, thyroid function, prothrombin time (PT), and activated partial prothrombin time (PTT), which remained within normal ranges in the supplement group. Organ histology remained unchanged. Although during the chronic toxicity period the triglyceride and LDL suppression persisted, it was noted that total cholesterol and HDL levels increased. The increase in cholesterol and HDL in the supplement group during chronic toxicity periods is simultaneous with loss of suppression of plasma levels of other liver function marker enzymes, ALT and AST, which are not involved in cholesterol synthesis. This possibly suggests that other liver enzymes involved in cholesterol synthesis, such as HMG-co A reductase, follow a similar escape from suppression.
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PMID:Acute and chronic toxicity study of fish oil and garlic combination. 1172 96

In this study, PMC (2,2,5,7,8-pentamethyl-6-hydroxychromane), a derivative of alpha-tocopherol, dose-dependently (1-10 mg/kg) ameliorated the increase in plasma aspartate aminotransferase (GOT) and alanine aminotransferase (GPT) levels caused by chronic repeated carbon tetrachloride (CCl4) intoxication in mice. Moreover, PMC significantly improved the CCl4-induced increase of hepatic glutathione peroxidase, reductase, and superoxide dismutase activities. PMC also restored the decrement in the glutathione content of hepatic tissues in CCl4-intoxicated mice. Furthermore, it also dose-dependently inhibited the formation of lipid peroxidative products during carbon tetrachloride treatment. Histopathological changes of hepatic lesions induced by carbon tetrachloride were significantly improved by treatment with PMC in a dose-dependent manner. These results suggest that PMC exerts effective protection in chronic chemical-induced hepatic injury in vivo.
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PMID:The protective effects of PMC against chronic carbon tetrachloride-induced hepatotoxicity in vivo. 1172 62

Feeding of 2% cholesterol diet increased lipid parameters in serum and tissues of rats during a period of one month. In addition to the above, lipid peroxidation also increased and activities of certain enzymes were significantly altered in the tissues. Similar changes were also observed to a greater extent with diets containing 40% by weight of coconut kernel or groundnut with and without 2% cholesterol. The enzymes studied were HMGCoA reductase, AST, ALT and ALP in tissues and serum as the case may be. In general the atherogenic effects were observed more with groundnut containing diets than those with coconut. Even though the oil from the former is mostly unsaturated and that from the latter is mostly saturated, these analytical criteria do not relate to their atherogenic effects. When 5% garlic was incorporated with any of the high fat diets, the lipid parameters, their peroxidation and alterations in enzyme activities were significantly decreased. These results show that garlic contains some principles that counteract the atherogenicity of the above oil seeds.
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PMID:Beneficial effects of garlic (Allium sativum Linn) on rats fed with diets containing cholesterol and either of the oil seeds, coconuts or groundnuts. 1201 59

It is established that galstena possesses hepatoprotector activity and is capable of reducing pathological changes in animals treated with toxic doses of antituberculous drugs. Galstena prevents from the development of cytolysis, as evidence by inhibition of the activity of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase. The anti cholestatic effect of galstena is confirmed by suppression of the growth in the levels of total bilirubin, alkaline phosphatase, and gamma-glutarate transpeptidase. Galstena was also found to possess antiinflammatory properties. Moreover, a growth in the activity of glutathione-dependent reductase (related to inhibited growth of the iron level in the blood serum) is evidence of the antioxidant activity. In addition, galstena prevents from an increase in the content of creatinine and urea, which is evidenced of decreasing endogenous intoxication.
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PMID:[Efficacy of galstena in liver damage induced by antitubercular agents]. 1210 99

The aim of this study was to investigate the effects of trauma on alterations in cytochrome P450 (CYP 450)-dependent drug metabolizing function and to determine the role of Kupffer cells in hepatocellular dysfunction. Rats underwent closed femur fracture (FFx) with associated soft-tissue injury under anesthesia, while control animals received only anesthesia. To deplete Kupffer cells in vivo, gadolinium chloride (GdCl3) was injected intravenously via the tail vein at 7.5 mg/kg body wt., 1 and 2 days prior to FFx surgery. At 72 h after FFx, serum alanine aminotransferase (ALT) activity was increased, and this increase was attenuated by GdCl3 pretreatment. Serum aspartate aminotransferase (AST) and lipid peroxidation levels were not changed by FFx. Hepatic microsomal CYP 450 content and aniline p-hydroxylase (CYP 2E1) activity were significantly decreased; decreases that were not prevented by GdCl3. The level of CYP 2B1 activity was decreased by Kupffer cell inactivation, but not by FFx. There were no significant differences in the activities of CYP 1A1, CYP 1A2 and NADPH-CYP 450 reductase among any of the experimental groups. Our findings suggest that FFx trauma causes mild alterations of hepatic CYP 450-dependent drug metabolism, and that Kupffer cells are not essential for the initiation of such injury.
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PMID:The roles of Kupffer cells in hepatocellular dysfunction after femur fracture trauma in rats. 1256 58

The lipid-lowering effects of 1-[2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-1,2,3,5-tetrahydro-2-oxo-5-(2,3-dimethoxyphenyl)-4,1-benzoxazepine-3-yl] acetyl] piperidin-4-acetic acid (TAK-475), a novel squalene synthase inhibitor, were examined in two models of familial hypercholesterolemia, low-density lipoprotein (LDL) receptor knockout mice and Watanabe heritable hyperlipidemic (WHHL) rabbits. Two weeks of treatment with TAK-475 in a diet admixture (0.02% and 0.07%; approximately 30 and 110 mg/kg/day, respectively) significantly lowered plasma non-high-density lipoprotein (HDL) cholesterol levels by 19% and 41%, respectively, in homozygous LDL receptor knockout mice. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin (in 0.02% and 0.07% admixtures), also reduced plasma levels of non-HDL cholesterol. In homozygous WHHL rabbits, 4 weeks of treatment with TAK-475 (0.27%; approximately 100 mg/kg/day) lowered plasma total cholesterol, triglyceride and phospholipid levels by 17%, 52% and 26%, respectively. In Triton WR-1339-treated rabbits, TAK-475 inhibited to the same extent the rate of secretion from the liver of the cholesterol, triglyceride and phospholipid components of very-low-density lipoprotein (VLDL). These results suggest that the lipid-lowering effects of TAK-475 in WHHL rabbits are based partially on the inhibition of secretion of VLDL from the liver. TAK-475 had no effect on plasma aspartate aminotransferase and alanine aminotransferase activities. Thus, the squalene synthase inhibitor TAK-475 revealed lipid-lowering effects in both LDL receptor knockout mice and WHHL rabbits.
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PMID:Lipid-lowering effects of TAK-475, a squalene synthase inhibitor, in animal models of familial hypercholesterolemia. 1267 52

Antrodia camphorata (A. camphorata) is well-known in Taiwan as a traditional Chinese medicine. The purpose of this study was to evaluate the ability of A. camphorata extracts to protect against oxidative stress in vitro and against carbon tetrachloride (CCl(4))-induced hepatic injury in vivo. An extract of A. camphorata inhibited nonenzymatic iron-induced lipid peroxidation in rat brain homogenates with an IC(50) value about 3.1 mg/mL. It also scavenged the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). The dose of the A. camphorata extract resulting in a decrease of 0.20 in the absorbance of DPPH was about 31 +/- 0.7 microg/mL. Furthermore, an A. camphorata extract dose-dependently (250-1250 mg/kg) ameliorated the increase in plasma aspartate aminotransferase (GOT) and alanine aminotransferase (GPT) levels caused by chronic repeated CCl(4) intoxication in mice. Moreover, A. camphorata extract significantly improved the CCl(4)-induced increase in hepatic glutathione peroxidase, reductase, and CCl(4)-induced decrease in superoxide dismutase activities. It also restored the decrement in the glutathione content and catalase activity of hepatic tissues in CCl(4)-intoxicated mice. Furthermore, it also dose-dependently inhibited the formation of lipid peroxidative products during CCl(4) treatment. Histopathological changes of hepatic lesions induced by CCl(4) were significantly ameliorated by treatment with an A. camphorata extract in a dose-dependent manner. These results suggest that A. camphorata extract exerts effective protection against chronic chemical-induced hepatic injury in vivo, by mediating antioxidative and free radical scavenging activities.
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PMID:Antioxidative and hepatoprotective effects of Antrodia camphorata extract. 1274 58

The response of fatty liver to stress conditions (t-butyl hydroperoxide [t-BH] or 36 h of fasting) was investigated by assessing intracellular glutathione (GSH) compartmentation and redox status, GSH peroxidase (GSH-Px) and reductase (GSSG-Rx) activities, lipid peroxidation (TBARs) and serum ALT levels in rats on a choline-deficient diet. Baseline cytosolic GSH was similar between fatty and normal livers, while the mitochondrial GSH content was significantly lower in fatty livers. With the except of cytosolic GSH-Px activity, steatosis was associated with significantly higher GSH-related enzymes activities. Liver TBARs and serum ALT levels were also higher. Administration of t-BH significantly decreased the concentration of cytosolic GSH, increased GSSG levels in all the compartments, and increased TBARs levels in cytosol and mitochondria and serum ALT; all these alterations were more marked in rats with fatty liver. Fasting decreased the concentration of GSH in all the compartments both in normal and fatty livers, increased GSSG, TBARs and ALT levels, and decreased by 50% the activities of GSH-related enzymes. Administration of diethylmaleimide (DEM) resulted in cytosolic and microsomal GSH pool depletion. Administration of t-BH to DEM-treated rats further affected cytosolic GSH and enhanced ALT levels, whereas the application of fasting to GSH depleted rats mainly altered the mitochondrial GSH system, especially in fatty livers. This study shows that fatty livers have a weak compensation of hepatic GSH regulation, which fails under stress conditions, thus increasing the fatty liver's susceptibility to oxidative damage. Differences emerge among subcellular compartments which point to differential adaptation of these organelles to fatty degeneration.
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PMID:Adaptation of subcellular glutathione detoxification system to stress conditions in choline-deficient diet induced rat fatty liver. 1501 60

Carbon tetrachloride feeding (3.2g/kg/72hr) for one month increased significantly the serum and tissue lipid profile and deranged the enzyme levels viz; alkaline phosphatase, alanine transaminase, aspartate transaminase, glutathionze reductase, HMGCoA reductase, catalase, gluc.6.PDH and malic enzyme in rats. Simultaneously the lipid peroxidation level in liver was also raised. On administration of garlic oil and its major nonpolar fraction (NPFGO) and a flavonoid isolated from the bark of Ficus bengalensis Linn, viz; leucopelargonin derivative respectively to different groups(100mg/kg/day) the deleterious effects of CCl4 were significantly ameliorated. The liver damage by CCl4 was satisfactorily prevented by these samples as effectively as Vit. E (50 mg/kg/day). The results prove that important nutraceuticals (phytonutrients) like bioflavonoids and theols i.e. allylic sulphide rich fractions give protection from toxins like CCl4. The order of beneficial effects of the drugs are Leucopelargonin > NPFGO > Garlic oil and their effects are comparable to that of vitamin E used at a minimal dose.
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PMID:Nutraceutical effects of garlic oil, its nonpolar fraction and a Ficus flavonoid as compared to vitamin E in CCl4 induced liver damage in rats. 1590 Sep 9


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