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)

Cyclosporine metabolites (CM) were compared with cyclosporine for their in vitro and in vivo immunosuppressive, nephrotoxic, and hepatotoxic effects using (A) in vitro mixed lymphocyte induction of monocyte/macrophage procoagulant activity (PCA), an accurate marker of allograft rejection; (B) in vitro toxic effects on renal cells in culture; and (C) a unidirectional rejection model of rat small intestinal transplantation (SIT). CM were composed of OL1, OL17, OL18, and two additional peaks C and H, (peak C: mass = 1235, 15.3% of total CM, peak H: mass = 1205, 6.3% of total CM). In vitro, CM fully suppressed the one-way mixed lymphocyte culture-induced PCA from 52.5 +/- 8.2 mU/10(6) PBM to the basal level 22.3 +/- 6.6 mU/10(6) PBM (P less than 0.01), which was comparable to CsA (21.3 +/- 5.5 mU/10(6) PBM). Lewis rats that had received Lewis-Brown Norway F1 hybrid intestinal allografts when treated with CM, demonstrated near-normal histology with minimal signs of rejection as compared with the fulminant clinical and histological rejection observed in the control (untreated and Cremaphor/NaCl treated) animals. PCA was markedly elevated in the control animals, 278 +/- 172 (untreated) and 160 +/- 98 mU/10(6) PBM (Cremaphor/normal saline treated), whereas CsA-treated allogeneic transplants expressed only basal levels of PCA (14.0 +/- 4 mU/10(6) PBM) (P less than 0.01), associated with normal histology. CM-treated animals expressed PCA levels of 27.0 +/- 10 mU/10(6) PBM, which was significantly different from both control and CsA-treated animals (P less than 0.01). In contrast to CsA-treated animals, CM-treated allogeneic transplants demonstrated no apparent renal or hepatic toxicity, as measured by blood urea nitrogen (25.3 +/- 9.5 vs. 10.0 +/- 5.3 mg/dl), alkaline phosphatase (160.7 +/- 29.3 vs. 100.3 +/- 19.5 U/L), and aspartate transaminase (96.7 +/- 23.7 vs. 61.7 +/- 11.7 U/L) (P less than 0.01). Similarly, in contrast to CsA, CM had minimal or no toxicity in renal epithelial and mesangial cells in culture, as measured by minimal or no inhibition of DNA, RNA, and protein synthesis. These results suggest that CM have potent immunosuppressive properties with no apparent nephrotoxicity and hepatotoxicity in vitro and in vivo.
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PMID:The effects of cyclosporine and cyclosporine metabolites in experimental small intestinal transplantation. 236 Feb 47

Cyclosporine blood levels were measured in 225 blood samples taken 14 days to 3 years after transplantation from 8 adult and 7 pediatric liver graft recipients. Results by high-performance liquid chromatography, radioimmunoassay with a polyclonal antibody (PARIA) or with a selective monoclonal antibody (MARIA) were compared in the context of major clinical events and alterations in serum bilirubin, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, urea, and creatinine. Cyclosporine blood levels by MARIA were significantly higher than HPLC values, but only by mean values of 11 micrograms/L in adult and 20 micrograms/L in pediatric patients. These differences were unaffected by alterations in liver or renal function and seem unlikely to affect clinical management. Minimum PARIA:HPLC ratios of 2-4 were noted in patients with good graft function, with higher ratios (up to 18) associated with hepatic dysfunction. Multiple regression analysis demonstrated that elevations in serum bilirubin and alkaline phosphatase significantly contributed toward the correlation with raised PARIA:HPLC ratios in adults and that gamma-glutamyl transpeptidase and aspartate aminotransferase were additionally important in children. There was no significant contribution from either serum urea or creatinine levels to raised PARIA:HPLC ratios, but in children a positive correlation existed between these indicators of renal function and trough cyclosporine concentrations determined by selective methods (HPLC and MARIA).
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PMID:Cyclosporine blood levels--an evaluation of radioimmunoassay with selective monoclonal or polyclonal antibodies and high-performance liquid chromatography in liver transplant recipients. 305 89

The use of cyclosporine long term after orthotopic liver transplantation has been analyzed in 73 adults with particular reference to the dose of drug used, either alone or in combination with other immunosuppressive agents, and the side effects observed. The first 22 patients were given cyclosporine 10 mg/kg/day for up to 2 years, but thereafter in these, and in all the other patients, the drug dose was regulated by whole blood trough levels. The proportion of patients maintained on cyclosporine alone increased from 11% at 3 months to 54.9% and 55.6% at 3 and 4 years, respectively. The dose of prednisolone used in combination with cyclosporine was lower than that used with azathioprine (P less than 0.05) up to 12 months after transplantation, but thereafter no significant difference was found. Acute cellular rejection was seen in 5 patients and in all instances was related to cessation of cyclosporine, while 10 patients developed chronic graft rejection manifested by the vanishing bile duct syndrome. At 12 months and onward, 54.5-73.3% of patients had normal serum bilirubin levels, and 47.6-80.0% had aspartate aminotransferase levels in the normal range. Cyclosporine was discontinued in 12 patients, in 8 cases because of impairment of renal function or hypertension. A trend toward rising serum creatinine levels was seen, and after 4 years on cyclosporine none of 12 patients had normal levels, and these exceeded 200 mumol/L in 5. The rise in creatinine levels was probably in part related to the higher doses used early in the study period. The incidence of hypertension progressively increased from 15.3% at 3 months to 63.6% at 4 years in patients maintained on cyclosporine.
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PMID:An analysis of cyclosporine efficacy and toxicity after liver transplantation. 327 83

In 16 patients with a renal allograft the activity concentrations of aspartate aminotransferase and alanine aminotransferase and the percentage stimulation of both enzymes were investigated. After the transplantation the patients received prednisone and cyclosporine A as immunosuppressive therapy, while exactly 3 months after the date of transplantation prednisone and azathioprine were given as immunosuppressives. In the first period, the percentage increase of the activity concentration of aspartate aminotransferase and alanine aminotransferase upon supplementation of pyridoxal-5'-phosphate in vitro were similar to that of healthy individuals. In the second period, however, the percentage increase of the activity concentration of alanine aminotransferase was much higher than that of aspartate aminotransferase. Cyclosporine A given during a period of about 400 days did not influence the percentage increase of both enzymes. It is concluded that the high stimulation of alanine aminotransferase in the second period depends on the presence of azathioprine or its metabolites in serum.
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PMID:Apoenzyme content of serum aminotransferases in patients with a renal allograft treated with cyclosporine A and azathioprine. 330 Oct 76

Cyclosporin A (CsA) treatment has been reported to cause rises in serum bile acids both in humans and rats. It has also been shown to suppress bile flow in situ in rats and inhibit the transport of bile salts by rat hepatocytes. The purpose of this study was to examine the influence of CsA on uptake of radiolabelled cholate (CA), glycocholate (GC) and taurocholate (TC) by isolated human hepatocytes. CsA did not significantly change Vmax for CA uptake [0.23 +/- 0.01 vs 0.25 +/- 0.02 nmol/mg protein/min for control and CsA (10 microM), respectively], but significantly increased Km (37 +/- 2 vs 86 +/- 8 microM). Similarly, Vmax for TC uptake was not affected (0.51 +/- 0.02 vs 0.67 +/- 0.05 nmol/mg protein/min) while Km was significantly increased [46 +/- 3 vs 109 +/- 11 microM for control and CsA (10 microM), respectively]. On the other hand, neither Vmax nor Km for GC uptake was affected by CsA. The data indicate a competitive pattern of inhibition induced by CsA on CA and TC uptake. Furthermore, CsA was found to cause a dose-related inhibition of accumulation of both cholate and taurocholate, but not GC accumulation. None of the concentrations of CsA showed a significant effect on the integrity of the human hepatocytes as assessed by ALT (alanine aminotransferase), AST (aspartate aminotransferase) and LDH (lactate dehydrogenase) release. The findings, in human hepatocytes, are generally consistent with the observations reported from rodent studies. They strongly support the contention that serum bile acid increases in CsA-treated patients are due to interference with the hepatocellular transport and accumulation of particular bile acids.
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PMID:Differential effects of cyclosporin A on the transport of bile acids by human hepatocytes. 837 35

Reoxygenation of rat-liver mitochondria after anoxic incubation induced release of matrix proteins. As assessed by release of a matrix enzyme, it was proportional to the rate of H2O2 production. The release was not observed with low concentrations of extramitochondrial free Ca2+, indicating a Ca(2+)-dependent pathway. Phospholipase A2 was not involved in the reoxygenation injury, because non-esterified fatty acids did not increase on reoxygenation even when re-acylation was inhibited and because inhibitors of phospholipase A2 had little effect on enzyme release. Cyclosporin A, ATP, ADP and inhibitors of pyridine nucleotide oxidation had a protective effect, strongly suggesting involvement of so-called Ca(2+)-dependent permeability transition. Ca2+ was also released from reoxygenated mitochondria and inhibition of reuptake of released Ca2+ attenuated the enzyme release. Similar releases of aspartate aminotransferase and Ca2+ were observed with mitochondria in an oxygen radical-generating system, hypoxanthine and xanthine oxidase. In this system, lecithin-cardiolipin liposomes also released entrapped Ca2+ without disruption of the membrane. From these results, we conclude that during reoxygenation, Ca2+ release and subsequent reuptake induced permeability transition of mitochondria, resulting in reoxygenation injury.
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PMID:Ca(2+)-induced, phospholipase-independent injury during reoxygenation of anoxic mitochondria. 841 80

Interferon (IFN) therapy is of proven efficacy in chronic hepatitis C, but it is not universally effective and is often limited by side effects. Cyclosporine A (CsA) is a potent immunosuppressant widely used in organ transplantation. We conducted a pilot study to determine whether CsA therapy could affect aminotransferase activity and hepatitis C virus RNA levels in patients with chronic hepatitis C. Cyclosporine A was administered to 10 patients (mean age of 59 years; male:female = 9:1) who did not respond to IFN therapy previously and who had elevated serum alanine aminotransferase (ALT) values for at least 6 months. All patients were positive for HCV-RNA by RT-PCR with genotype 1b. Their mean duration of hepatitis was 15 years. Oral CsA was given for 3 months in a dose that was increased at 1 month intervals from 1.5-2.0 to 2.0-3.0 and 3.0-4.0 mg/kg per day. All patients completed the treatment schedule, although two patients developed mild non-symptomatic hypertension. Serum ALT levels gradually decreased in all but one patient. The mean percentage decrease was 59.5% at the end of therapy (from 153 +/- 82 to 62 +/- 48 IU/L; P < 0.02). The ALT levels fell to the normal range in five patients, although once therapy was discontinued the enzyme levels tended to return to pretreatment levels. Serum aspartate aminotransferase and g-glutamyl transpeptidase levels similarly decreased. The serum HCV-RNA titre, determined by competitive RT-PCR, did not change in any patient throughout the study period. There were no appreciable alterations in other laboratory tests, such as serum creatinine levels and lymphocyte subsets, except for an increase in serum alkaline phosphatase levels. These findings suggest that CsA, even in a relatively low dose, reduces serum aminotransferase levels without serious side effects in patients with chronic hepatitis C, although an antiviral effect was not noted.
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PMID:Cyclosporine therapy affects aminotransferase activity but not hepatitis C virus RNA levels in chronic hepatitis C. 907 26

We have investigated the effect of thyroid hormone on the mitochondrial membrane permeability properties in a hypothyroid rat model. The role played by calcium in affecting these properties has been also examined. Cyclosporin A-sensitive mitochondrial calcium efflux, swelling, and external release of matrix proteins are events that occur normally during the permeability transition process induced by calcium loading of mitochondria. We demonstrate that these events are impaired in mitochondria isolated from the liver of hypothyroid rats, even in the presence of high calcium content. However, after thyroid hormone administration to hypothyroid rats, the mitochondrial permeability transition process in response to calcium loading is restored. Consequently, mitochondrial calcium efflux, swelling, and release of matrix proteins, like glutamate dehydrogenase, malate dehydrogenase, and aspartate aminotransferase occur. These effects are abrogated by the concomitant administration of cyclosporin A. The results of the present study suggest that hypothyroidism may be a potential source of adverse effects in patients receiving cyclosporin A.
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PMID:Thyroid hormone administration to hypothyroid rats restores the mitochondrial membrane permeability properties. 1293 49

We have investigated the effect of thyroid hormone on recovery of liver mass and on the mitochondrial membrane permeability properties during rat liver regeneration after 70% partial hepatectomy (PH). In the euthyroid state, liver weight starts to recover 24 h after PH and is completely restored 96 h after PH. Cyclosporin A (CsA)-sensitive mitochondrial permeability transition (MPT) occurs 24 h after PH, and it has been suggested to act in the signaling mechanism for hepatocyte proliferation. In this study we show that hypothyroidism delays recovery of the liver mass, being only 50% of the initial weight 96 h after PH, and alters the duration and mode of MPT occurrence, first inducing a CsA-insensitive swelling 24 h after PH, followed by a CsA-sensitive swelling 96 h after PH. The occurrence of both CsA-sensitive and -insensitive swelling is shown to be associated with an increase in mitochondrial calcium content. Concurrent with mitochondrial swelling, external release of matrix proteins from mitochondria, such as aspartate aminotransferase and malate dehydrogenase, is shown to be CsA insensitive 24 h after PH and CsA sensitive 96 h after PH. After thyroid hormone administration to hypothyroid rats, the liver regenerative capacity is restored, and the duration and mode of MPT occurrence as well as changes in mitochondrial calcium content become similar to those observed in the euthyroid condition. The results of the present study suggest the involvement of a mitochondria-mediated pathway in regulation of the liver regenerative process by thyroid hormone.
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PMID:Thyroid hormone treatment of hypothyroid rats restores the regenerative capacity and the mitochondrial membrane permeability properties of the liver after partial hepatectomy. 1530 17

The present study was designed to evaluate the possible beneficial effect of lipoic acid in preventing the renal damage induced by cyclosporine A in rats. Male albino rats of Wistar strain were divided into four groups and treated as follows. Two groups received cyclosporine A by oral gavage (25 mg/kg/body weight) for 21 days to induce nephrotoxicity, one of which simultaneously received lipoic acid treatment (20 mg/kg body weight) for 21 days. A vehicle (olive oil) and a lipoic acid drug control were also included. Cyclosporine A induced renal damage was evident from the decreased activities of tissue marker enzymes (alkaline phosphatase, acid phosphatase, lactate dehydrogenase, aspartate transaminase and alanine transaminase) and decreased activities of ATPases (Na+, K+-ATPase, Ca2+-ATPase and Mg2+ ATPase). An apparent increase in the levels of serum constituents (urea, uric acid and creatinine) and urinary marker enzymes (N-acetyl-beta-D-glucosaminidase, beta-glucosidase, beta-galactosidase, cathepsin-D and gamma-glutamyl transpeptidase) along with significant decline in creatinine clearance were seen in the cyclosporine treated rats, which was reversed upon treatment with lipoic acid. Ultrastructural observations were also in agreement with the above abnormal changes. Lipoic acid effectively reverted these abnormal biochemical changes and minimized the morphological lesions in renal tissue. Hence, this study clearly exemplifies that lipoic acid might be an ideal choice against cyclosporine A induced cellular abnormalities.
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PMID:Therapeutic efficacy of DL-alpha-lipoic acid on cyclosporine A induced renal alterations. 1761 14


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