Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Procaine has previously been shown to diminish the nephrotoxicity of cisplatin and the nephrotoxic effects of cisplatin and a new cisplatin complex (cis-diamminechloro-[2-(diethylamino) ethyl-4-aminobenzoate, N4]-chlorideplatinum (II) monohydrochloride monohydrate; DPR), that contains procaine hydrochloride were compared with rat renal cortical slices. 2. Cisplatin at 1 mM caused toxicity to the slices, as shown by an increase in the leakage of aspartate aminotransferase and lactate dehydrogenase from the slices into the incubation medium and a decrease in the reduction of a tetrazolium dye (MTT assay). Addition of procaine (1 mM) protected against cisplatin-induced toxicity. DPR either at 1 mM or at 4 mM had no effect either on the enzyme leakage or MTT reduction by the renal slices, but DPR at 10 mM produced a similar magnitude of enzyme leakage to cisplatin (1 mM). 3. DPR lowered the concentration of ATP and glutathione (GSH) in the slices but was less potent than cisplatin. Thiobarbituric acid reactive substances, indicators of lipid peroxidation, released into the medium were increased by the highest concentration of DPR (10 mM), which suggests that DPR has the potential to cause oxidative stress. 4. The results suggest that DPR was far less toxic than either cisplatin alone or a mixture of cisplatin and procaine.
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PMID:Comparison of the toxicities of cisplatin and a new cisplatin-procaine complex to rat renal cortical slices. 884 12

The protective effect of N-(2-mercaptopropionyl)-glycine (tiopronin), a clinically used sulfhydryl-containing compound, on cisplatin-induced toxicity to rat renal cortical slices was investigated. Exposure of the slices to cisplatin (2 mM) resulted in toxicity, as shown by an increase in leakage of the two enzymes aspartate aminotransferase and lactate dehydrogenase into the incubation medium and a time-dependent decrease in the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) by the slices. Tiopronin (2 mM) completely prevented the cisplatin-induced increase in enzyme leakage and substantially blocked the decrease of MTT reduction caused by cisplatin. These protective effects were concentration-dependent and furthermore, the depletion of ATP, glutathione and induction of lipid peroxidation in the slices by cisplatin (2 mM) were reversed by 2 mM tiopronin. Pretreatment of slices with tiopronin for 60 min also significantly protected the renal slices from cisplatin-induced toxic effects. These protective effects, however, were abolished by p-aminohippuric acid, a compound with some structural similarity to tiopronin, which both undergoes and inhibits active transport in the cells of the proximal convoluted tubule. Cisplatin (1 mM) also depleted the free sulfhydryls of tiopronin (1 mM) in a second incubation medium system and PAH (2 mM) diminished the extent of this depletion somewhat. These observations suggest that tiopronin protects against cisplatin-induced nephrotoxicity by acting as an alternative target for cisplatin both intra- and extracellularly and thus protects against cisplatin-induced depletion of glutathione in the kidney cell.
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PMID:Tiopronin protects against the nephrotoxicity of cisplatin in rat renal cortical slices in vitro. 897 67

The hepato-steatogenic compound ethionine has been used to investigate the correlations between in vivo and in vitro toxicity data. The aim was to find a suitable model of toxicity in hepatocyte suspensions or monolayers in vitro, which could predict the known toxicity of ethionine in vivo and which could be implemented in screening compounds of unknown toxicity. Thus a variety of markers of cytotoxicity, metabolic competence and liver-specific functions were investigated in rat hepatocyte suspensions and monolayers and compared with in vivo data in the rat. The following markers were measured in the appropriate system: (1) Neutral red uptake; 3-(4,5 dimethyl)thiazol-2-yl,-2,5-diphenyl tetrazolium bromide (MTT) reduction; lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) leakage (cytotoxicity). (2) ATP levels, protein synthesis and glutathione (GSH) levels (metabolic competence). (3) Urea and triglyceride synthesis and beta-oxidation (liver specific functions). Ethionine (0-30 mM) did not affect the markers of direct cytotoxicity, except neutral red uptake, which was reduced by 18 and 30 mM ethionine after 20 h in culture. ATP and GSH depletion occurred in hepatocyte suspensions at the highest concentrations of ethionine (20 and 30 mM) after 1 h. In monolayers, GSH levels were reduced after 4 h, but not 20 h. Urea synthesis was increased in hepatocyte suspensions from 1 to 3 h by 10-30 mM ethionine and reduced after 20 h in cultured hepatocytes (18-30 mM). Protein synthesis was reduced and beta-oxidation was increased in ethionine-treated hepatocyte suspensions. Unfortunately, there was no measurable effect on triglyceride accumulation within cells (the major biochemical change in vivo) in either system. Ethionine treated hepatocytes in suspension showed the same rate of triglyceride synthesis and transportation out of cells as control cells. Thus, hepatocyte suspensions were able to mimic the early biochemical effects of ethionine in vivo (ATP and GSH depletion, inhibition of protein synthesis) and some effects on urea synthesis, but monolayer cultures appeared to be less sensitive to the toxicity of ethionine. However, neither in vitro system was able to model the effects of ethionine on the accumulation of triglycerides in vivo.
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PMID:Ethionine toxicity in vitro: the correlation of data from rat hepatocyte suspensions and monolayers with in vivo observations. 980 31

Human skin equivalent cultures were investigated as possible pre-clinical skin irritation screens to aid safety assessments for chemicals and product formulations, and to facilitate design of safe and efficient human studies. In vitro responses in human skin equivalent cultures were compared directly to in vivo human skin responses from historic or concurrent skin tests for representative chemicals and products, including surfactants, cosmetics, antiperspirants, and deodorants. The in vivo data consisted of visual scores (i.e., erythema and edema) from skin-patch tests and diary accounts of skin irritation from product-use studies. In the in vitro studies, cornified, air-interfaced human skin cultures (EpiDerm) were evaluated using methods designed to parallel human clinical protocols with topical dosing of neat or diluted test substances to the stratum corneum surface of the skin cultures. The in vitro endpoints have previously been shown to be relevant to human skin irritation in vivo, including the MTT metabolism assay of cell viability, enzyme release (lactate dehydrogenase and aspartate aminotransferase), and inflammatory cytokine expression (Interleukin-1alpha). For surfactants, dose-response curves of MTT cell-viability data clearly distinguished strongly-irritating from milder surfactants and rank-ordered irritancy potential in a manner similar to repeat-application (3x), patch-test results. For the antiperspirant and deodorant products, all the in vitro endpoints correlated well with consumer-reported irritation (r, 0.75-0.94), with Interleukin-1alpha (IL-1alpha) release, showing the greatest capacity to distinguish irritancy over a broad range. IL-1alpha release also showed the best prediction of human skin scores from 14-day cumulative irritancy tests of cosmetic products. These results confirm the potential value of cornified human skin cultures as in vitro pre-clinical screens for prediction of human skin irritation responses. A preliminary report of these results has been published.
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PMID:Comparison of in vitro and in vivo human skin responses to consumer products and ingredients with a range of irritancy potential. 1035 13

The effects of 6-formylpterin on tumor necrosis factor (TNF)-alpha-induced apoptotic cell injury were studied in cultured rat hepatocytes. The incubation of the hepatocytes with TNF-alpha and actinomycin D (ActD) induced the apoptotic cell injury. The level of aspartate transaminase (AST) in the culture supernatant increased, and the cell viability, estimated by mitochondrial respiration (MTT assay), decreased. The DNA fragmentation and the caspase 3-like activity, which are characterized to apoptosis, increased. When the hepatocytes were incubated with 100-500 microM 6-formylpterin, the intracellular formation of reactive oxygen species (ROS) was observed, and the ratio of reduced and oxidized glutathione (GSH/GSSG) of whole cell lysate decreased. The co-incubation of the TNF-alpha/ActD-treated hepatocytes with 100-500 microM 6-formylpterin attenuated the TNF-alpha/ActD-induced apoptotic cell injury. The level of AST decreased and the cell viability increased. Both the DNA fragmentation and the caspase 3-like activity decreased. The caspases, executors of apoptosis, are known to require a reduced cystein in their active site to function, and the intact intracellular GSH/GSSG is essential for the caspase activation. Therefore, our findings suggest that intracellular ROS generated by 6-formylpterin decline the intracellular redox state to an oxidant state, which suppresses the caspase activity and prevents the apoptotic cell injury of hepatocytes.
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PMID:Protective effects of intracellular reactive oxygen species generated by 6-formylpterin on tumor necrosis factor-alpha-induced apoptotic cell injury in cultured rat hepatocytes. 1596 7

The biological activity of methanolic and aqueous extracts from dehydrated hypocotyls of Lepidium meyenii (Brassicaceae, vernacular name "maca"), was studied on rat hepatocytes and human breast cancer MCF-7 cells. The extracts did not exhibit cytotoxicity in hepatocyte primary cultures up to 10 mg/ml as measured by the MTT viability test, and lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) leakage. Moreover, after 72 h, extracts inhibited LDH and AST leakage from the hepatocytes. When hepatocytes were intoxicated by t-butyl hydroperoxide, neither extract prevented oxidative damage. Both extracts showed weak antioxidant activity in the DPPH radical scavenging test with IC(50) values of 3.46 +/- 0.16 and 0.71 +/- 0.10 mg/ml, for aqueous and methanolic extracts, respectively. Thus, the observed effect on spontaneous enzyme leakage is probably mediated through mechanisms other than antioxidant activity. Both methanolic and aqueous extracts have shown estrogenic activity comparable with that of silymarin in MCF-7 cell line. Maca estrogenicity was exhibited in the range from 100 to 200 mug of extract per ml. The findings in the present study show that maca does not display in vitro hepatotoxicity. In contrast, a slight cytoprotective effect, probably not mediated by antioxidant capacity, was noted. Maca extracts exhibited estrogenic activity comparably to the effect of silymarin in MCF-7 cells.
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PMID:The in vitro biological activity of Lepidium meyenii extracts. 1652 48

Butterbur extracts (Petasites hybridus) are recommended for the prevention of migraine, but pharmacovigilance reports may be suggestive of rare hepatobiliary toxicity. To evaluate its hepatotoxic potential, a series of in vivo and in vitro studies were carried out. Essentially, there were no signs of hepatocellular toxicity at estimated therapeutic C(max) levels of 60 ng/ml. Nonetheless, in a 28-day toxicity study at approximately 200-fold of therapeutic doses, induced liver transaminases and bilirubin elevations were observed. In a subsequent 6-month chronic toxicity study, the initial hepatobiliary effects were reproduced, but at the end of the study, liver function recovered and returned to normal as evidenced by clinical chemistry measurements. To identify possible mechanisms of hepatotoxicity, we investigated liver function in vitro at > 170-fold of therapeutic C(max) levels, including cytotoxicity (lactate dehydrogenase, MTT, and ATP), transaminase activities (alanine aminotransferase and aspartate aminotransferase), albumin synthesis, urea and testosterone metabolism to assay for cytochrome P450 monooxygenase activity. Only with extracts rich in petasin (37% petasin) and at high and well above therapeutic doses, liver toxicity was observed. A toxicogenomic approach applied to hepatocyte cultures enabled hypothesis generation and was highly suggestive for extracts high in petasin content to impair bile acid transport and lipid and protein metabolism. Importantly, neither chronic rat in vivo nor rat in vitro studies predicted reliably hepatotoxicity, therefore reemphasizing the utility of human-based in vitro investigations for the development of safe medicinal products. Finally, toxicogenomics enabled the characterization of a novel butterbur extract with no signals for hepatotoxicity.
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PMID:Toxicogenomics applied to cultures of human hepatocytes enabled an identification of novel petasites hybridus extracts for the treatment of migraine with improved hepatobiliary safety. 1977 Apr 83

The hepatotoxicity induced by valproic acid (VPA) has been described in many clinical studies and the related mechanism has been partly elucidated. The objective of this study is to investigate the hepatotoxicity and its underlying mechanism of valproic acid on human hepatoma carcinoma cell line HepG2. The cell viability was evaluated by 3-(4,5-dimethyltyiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in the medium were detected using spectrophotometry. The gene expressions of cytochrome P450 1 A1 (CYP1A1), ATP-binding cassette transporter G1 (ABCG1) and carnitine palmitoyltransferase 1 (CPT1A), related to lipid transport and fatty acid metabolism, were measured by quantitative real-time reverse transcriptase-PCR. Treatment with valproate sodium obviously decreased the viability of HepG2 cells, accompanied by the increased leakages of ALT, AST and LDH in a dose-dependent manner. Furthermore, the gene expressions of CYP1A1, ABCG1 and CPT1A were almost up-regulated in the treated groups. In conclusion, these data suggest that VPA-induced hepatotoxicity was critically enhanced with the elevation of valproate sodium, which may be correlated with up-regulated gene expressions of CYP1A1, ABCG1 and CPT1A.
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PMID:Participation of lipid transport and fatty acid metabolism in valproate sodium-induced hepatotoxicity in HepG2 cells. 2037 Dec 85

Cell cultures are a potentially useful model to predict in vivo oral mucosa irritation. To this end, oral mucosa organ equivalent cultures (OMOEC) and skin equivalent cultures (SEC), both derived from human tissue, were evaluated for their responsiveness to test dentifrices with graded degrees of irritation potential. OMOEC and SEC were treated with test dentifrices and responses were evaluated by histopathology, cell viability (MTT incorporation), and cytotoxicity [release of aspartate aminotransferase (AST)]. Cell viability in OMOEC and SEC was reduced in a dose- and time-dependent manner in response to the test dentifrices. Correspondingly, AST release was increased in a dose- and time-dependent manner in response to the test dentifrices. These results demonstrate that OMOEC and SEC systems respond linearly to graded degrees of irritation potential as represented by generic dentifrices. Such results in an in vitro model of oral mucosa irritation allow direct comparison of in vitro responses with those obtained in an in vivo model, thus providing the groundwork for a tiered approach to assessment of irritation potential of oral care products.
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PMID:In vitro oral mucosa irritation testing with human cell cultures. 2065 64

Medicinal plants play a key role in human health care. Frustration over the side effects of allopathic drugs has driven the medical world to take asylum in the plant kingdom for the treatment of various ailments. Euphorbia hirta belonging to the family of Euphorbiacae has been reported to possess antibacterial, antiviral, and anticancer activity. The aim of the present study was to investigate the protective effect of E. hirta against antitubercular drug-induced cytotoxicity in freshly isolated hepatocytes. The extent of cytotoxicity of the plant extracts was also analyzed using human liver derived HepG2 cell line by estimating the viability of cells (MTT assay). The alcoholic plant extract normalized the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), triacylglycerol (TAG), cholesterol, total protein, albumin, total and direct bilirubin, which were altered due to antitubercular drug intoxication. A dose-dependent increase in percent viability was observed when antitubercular drug exposed HepG2 cells were treated with different concentrations of plant extracts (125, 250, 500 and 1000 microg/mL) which were compared with a standard hepatoprotective drug silymarin. The highest percentage viability of HepG2 was observed at a concentration of 1000 microg/mL. The results suggest that E. hirta exerts protection against antitubercular drug-induced cytotoxicity in this vitro model system.
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PMID:Protective potential [correction of potencial] of Euphorbia hirta against cytotoxicity induced in hepatocytes and a HepG2 cell line. 2130 54


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