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)

The anticancer drug cisplatin is nephrotoxic and neurotoxic. Previous data support the hypothesis that cisplatin is bioactivated to a nephrotoxicant. The final step in the proposed bioactivation is the formation of a platinum-cysteine S-conjugate followed by a pyridoxal 5'-phosphate (PLP)-dependent cysteine S-conjugate beta-lyase reaction. This reaction would generate pyruvate, ammonium, and a highly reactive platinum (Pt)-thiol compound in vivo that would bind to proteins. In this work, the cellular location and identity of the PLP-dependent cysteine S-conjugate beta-lyase were investigated. Pt was shown to bind to proteins in kidneys of cisplatin-treated mice. The concentration of Pt-bound proteins was higher in the mitochondrial fraction than in the cytosolic fraction. Treatment of the mice with aminooxyacetic acid (AOAA, a PLP enzyme inhibitor), which had previously been shown to block the nephrotoxicity of cisplatin, decreased the binding of Pt to mitochondrial proteins but had no effect on the amount of Pt bound to proteins in the cytosolic fraction. These data indicate that a mitochondrial enzyme catalyzes the PLP-dependent cysteine S-conjugate beta-lyase reaction. PLP-dependent mitochondrial aspartate aminotransferase (mitAspAT) is a mitochondrial enzyme that catalyzes beta-elimination reactions with cysteine S-conjugates of halogenated alkenes. We reasoned that the enzyme might also catalyze a beta-lyase reaction with the cisplatin-cysteine S-conjugate. In this study, mitAspAT was stably overexpressed in LLC-PK(1) cells. Cisplatin was significantly more toxic in confluent monolayers of LLC-PK(1) cells that overexpressed mitAspAT than in control cells containing vector alone. AOAA completely blocked the cisplatin toxicity in confluent mitAspAT-transfected cells. The Pt-thiol compound could rapidly bind proteins and inactivate enzymes in close proximity of the PLP-dependent cysteine S-conjugate beta-lyase. Treatment with 50 or 100 microM cisplatin for 3 h, followed by removal of cisplatin from the medium for 24 h, resulted in a pronounced loss of alpha-ketoglutarate dehydrogenase complex (KGDHC) activity in both mitAspAT-transfected cells and control cells. Exposure to 100 microM cisplatin resulted in a significantly greater loss of KGDHC activity in the cells overexpressing mitAspAT than in control cells. Aconitase activity was diminished in both cell types, but only at the higher level of exposure to cisplatin. AspAT activity was also significantly decreased by cisplatin treatment. By contrast, several other enzymes (both cytosolic and mitochondrial) involved in energy/amino acid metabolism were not significantly affected by cisplatin treatment in the LLC-PK(1) cells, whether or not mitAspAT was overexpressed. The susceptibility of KGDHC and aconitase to inactivation in kidney cells exposed to cisplatin metabolites may be due to the proximity of mitAspAT to KGDHC and aconitase in mitochondria. These findings support the hypothesis that a mitochondrial cysteine S-conjugate beta-lyase converts the cisplatin-cysteine S-conjugate to a toxicant, and the data are consistent with the hypothesis that mitAspAT plays a role in the bioactivation of cisplatin.
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PMID:Cisplatin-induced toxicity is associated with platinum deposition in mouse kidney mitochondria in vivo and with selective inactivation of the alpha-ketoglutarate dehydrogenase complex in LLC-PK1 cells. 1684 39

Methanococcus maripaludis and Methanocaldococcus jannaschii produce cysteine for protein synthesis using a tRNA-dependent pathway. These methanogens charge tRNA(Cys) with l-phosphoserine, which is also an intermediate in the predicted pathways for serine and cystathionine biosynthesis. To establish the mode of phosphoserine production in Methanococcales, cell extracts of M. maripaludis were shown to have phosphoglycerate dehydrogenase and phosphoserine aminotransferase activities. The heterologously expressed and purified phosphoglycerate dehydrogenase from M. maripaludis had enzymological properties similar to those of its bacterial homologs but was poorly inhibited by serine. While bacterial enzymes are inhibited by micromolar concentrations of serine bound to an allosteric site, the low sensitivity of the archaeal protein to serine is consistent with phosphoserine's position as a branch point in several pathways. A broad-specificity class V aspartate aminotransferase from M. jannaschii converted the phosphohydroxypyruvate product to phosphoserine. This enzyme catalyzed the transamination of aspartate, glutamate, phosphoserine, alanine, and cysteate. The M. maripaludis homolog complemented a serC mutation in the Escherichia coli phosphoserine aminotransferase. All methanogenic archaea apparently share this pathway, providing sufficient phosphoserine for the tRNA-dependent cysteine biosynthetic pathway.
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PMID:Biosynthesis of phosphoserine in the Methanococcales. 1707 63

Since the 1980's nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H(2)S), the endogenous gas molecules produced from metabolic pathway, have been realized as signal molecules to be involved in the regulation of body homeostasis and to play important roles under physiological and pathophysiological conditions. The researches on these endogenous gas signal molecules opened a new avenue in life science. To explore the new member of gasotransmitter family, other endogenous gas molecules which have been regarded as metabolic waste up to date, and their biological regulatory effects have been paid close attention to in the current fields of life science and medicine. Sulfur dioxide (SO(2)) can be produced endogenously from normal metabolism of sulfur-containing amino acids. L-cysteine is oxidized via cysteine dioxygenase to L-cysteinesulfinate, and the latter can proceed through transamination by glutamate oxaloacetate transaminase (GOT) to beta-sulfinyl pyruvate which decomposes spontaneously to pyruvate and SO(2). In mammals, activated neutrophils by oxidative stress can convert H(2)S to sulfite through a reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase-dependent process. The authors detected endogenous production of SO(2) in all cardiovascular tissues, including in heart, aorta, pulmonary artery, mesenteric artery, renal artery, tail artery and the plasma SO(2) content. As the key enzyme producing SO(2), GOT mRNA in cardiovascular system was detected and found to be located enriched in endothelial cells and vascular smooth muscle cells near the endothelial layer. When the normal rats were treated with hydroxamate(HDX), a GOT inhibitor, at a dose of 3.7 mg/kg body weight, the blood pressure (BP) went high markedly, the ratio of wall thickness to lumen radius was increased by 18.34%, and smooth muscle cell proliferation was enhanced. The plasma SO(2) level in the rats injected with 125 micromol/kg body weight SO(2) donor was increased to 721.98+/-30.11 micromol/L at the end of 30 seconds, while the blood pressure was decreased to the lowest point 65.0+/- 4.9 mm Hg at the end of 1 minute. The above results showed that endogenous SO(2) might be involved in the maintenance of blood pressure and normal vascular structure. In spontaneous hypertensive rat (SHR) animal model, exogenous supplement of SO(2) donor decreased the BP, the media cross-sectional area, and pressure of the media and the ratio of wall thickness to lumen radius in the SHR. Moreover, the proliferative index of aortic smooth muscle cells was decreased in the SHR treated with SO(2) donor compared with that in SHR. The above data showed that SO(2) could prevent the aortic structural remodeling by inhibiting the proliferation of aortic smooth muscle cells. The authors observed the direct vasorelaxant effects of SO(2) on the aortic ring pre-treated with norepinephrine (NE). SO(2) donor at a concentration of 25-100 micromol/L relaxed the aortic ring temporarily and slightly, but SO(2) donor at a concentration of 1-12 mmol/L induced relaxation of the ring in a concentration-dependent manner. Administration with nicardipine, an L-type calcium channel blocker other than glibenclamide, an ATP sensitive potassium channel (K(ATP) channel) blocker or removal of vascular endothelium could decrease the SO(2)-induced vasorelaxation. In hypoxic pulmonary hypertension animal model, SO(2) donor decreased the mean pulmonary artery pressure and the systolic pulmonary artery pressure (P<0.01), respectively as compared with hypoxic group, and alleviated obviously the hypoxic pulmonary vascular structural remodeling. The percentage of muscularized arteries of small pulmonary vessels was significantly decreased in hypoxia+SO(2) donor-treated rats compared with that of hypoxic rats (P<0.01), while the percentage of non-muscularized vessels was obviously higher in hypoxia with SO(2) donor-treated rats than that of hypoxic rats (P<0.01). Similarly, SO(2) obviously decreased relative media area and relative media thickness of small muscularized pulmonary arteries in hypoxic rats (P<0.01). The above data showed that SO(2) might play an important role in development of hypoxic pulmonary hypertension. Perfusion with SO(2) donor (10(-6)-10(-3) mol/L) to the isolated rat heart obviously inhibited the left ventricular peak rate of contraction ( + LV dp/ dtmax) , peak rate of relaxation (-LV dp/ dtmax) and difference of left ventricular pressure ( DeltaLVP) in a concentration dependent manner. Nicardipine, an L-type calcium channel blocker, could partly antagonize the inhibitory effect of SO(2) on the heart function. In a word, SO(2) could be endogenously generated in cardiovascular tissues and exert important cardiovascular effects such as vasorelaxant effect and negative inotropic effects. Moreover, SO(2) might play considerable roles in the regulation of systemic circulatory pressure, pulmonary circulatory pressure and vascular structural remodeling in the pathogenesis of hypertension and hypoxic pulmonary hypertension. On the basis of the above findings, we presumed that endogenous SO(2) might be a novel cardiovascular functional regulatory gasotransmitter. More studies on the significance of endogenous SO(2) in cardiovascular system under physiological and pathophysiological conditions need to be investigated.
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PMID:[Significance of endogenous sulfur dioxide in the regulation of cardiovascular system]. 1765 74

Allogeneic hematopoietic stem cell transplantation (ASCT) and its conditioning with chemoradiotherapy often results in liver toxicity, the most severe form being veno-occlusive liver disease (VOD). N-acetyl-L-cysteine (NAC), an antioxidant glutathione precursor, may provide protection from liver toxicity. Patients with elevated bilirubin (>26 mmol/l) and/or elevated (ALT) (>1.4 microkat/l) and/or aspartate aminotransferase (AST) (>1.4 microkat/l) levels were randomized to treatment with NAC or no treatment. Among 522 transplanted patients, 160 were included in the trial. NAC was given, 100 mg/kg per day, as a 6-h i.v. infusion until normalization of bilirubin, ALT and AST values. Maximum bilirubin level was the same in patients randomized to NAC (n=72) or controls (n=88). Increase and recovery of ALT and AST were the same in patients randomized to NAC or controls. There were two patients in the NAC group who developed VOD, as compared to three of the controls. To conclude, NAC does not improve liver toxicity after ASCT.
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PMID:A prospective randomized study using N-acetyl-L-cysteine for early liver toxicity after allogeneic hematopoietic stem cell transplantation. 1817 10

Efficacy of thiol chelators viz. N-acetyl cysteine and D-penicillamine (NAC and DPA) along with nutritional supplements viz. zinc acetate, sodium selenite and magnesium sulphate (Zn, Se and Mg) in the treatment of mercury intoxication was investigated in rats. This is of particular interest since high bonding affinity between mercuric ion and the thiol group exits. The mutual antagonism of mercury and selenium is one of the strongest examples of the interaction in the trace element field. Adult rats of Sprague-Dawley strain were administered a bolus dose of dimethyl mercury (10 mg/kg) orally. A significant rise in the aspartate aminotransferase, alanine aminotransferase, serum alkaline phosphatase, lactate dehydrogenase, gamma glutamyltranspeptidase, bilirubin and creatinine were observed. Single mercury exposure also resulted in a significant increase in lipid peroxides with a concomitant decrease in reduced glutathione level in liver, kidney and brain. A decrease in the enzymatic activities of acetyl cholinesterase in different regions of the brain was observed. These parameters were restored considerably with chelating agents along with nutritional supplementation, but NAC+Se and DPA+Mg offered significant protection in comparison with other combinations.
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PMID:Effect of monothiol along with antioxidant against mercury-induced oxidative stress in rat. 1825 9

Sanguinarine (SANG) has been suggested to be one of the principle constituents responsible for the toxicity of Argemone mexicana seed oil. In this study, we focused on the possible mechanism of SANG-induced hepatotoxicity. The serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) activities, hepatic vacuolization, lipid accumulation and lipid peroxidation of the liver were increased, and triglyceride (TG) was decreased in SANG-treated mice (10 mg kg(-1) i.p.), indicating damage to the liver. SANG induced cell death and DNA fragmentation, in a concentration- (0-30 microm) and time-dependent (0-24 h) manner, and the cytotoxicity of SANG (15 microm) was accompanied by an increase in reactive oxygen species and a lessening in protein thiol content; these outcomes were reversed by glutathione, N-acetyl-l-cysteine and 1,4-dithiothretol, and slightly improved by other antioxidants in hepatocytes. SANG can affect the function of mitochondria, leading to the depletion of the mitochondrial membrane potential and adenosine 5'-triphosphate content of hepatocytes. SANG caused an uncoupling effect of the respiratory chain at lower concentrations, but inhibited the respiratory chain at higher concentrations in mitochondria isolated from rat liver. In conclusion, the data suggest that SANG is a liver toxin that induces cytotoxicity in liver cells, possibly through oxidation of protein thiols, resulting in oxidative stress on the cells and disturbance of mitochondrial function.
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PMID:Induction of hepatotoxicity by sanguinarine is associated with oxidation of protein thiols and disturbance of mitochondrial respiration. 1854 46

Acetaminophen (APAP) overdose is often fatal, leading to fulminant hepatic and renal tubular necrosis in humans and animals. We studied the effect of a nutrient mixture (NM) containing, among other nutrients, lysine, proline, ascorbic acid, N-acetyl cysteine, and green tea extract, which has previously been demonstrated to exhibit a broad spectrum of therapeutic properties on APAP-induced hepatic and renal damage in ICR (Imprinting Control Region) mice. Seven-week-old male ICR mice were divided into four groups (A-D) of five animals each. Groups A and C mice were fed a regular diet for 2 weeks, while groups B and D mice were supplemented with 0.5% NM (w/w) during that period. Groups A and B received saline i.p., while groups C and D received APAP (600 mg/kg) i.p. All animals were killed 24 h after APAP administration, serum was collected to assess the liver and kidney functions, and the livers and kidneys were excised for histology. Mean serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, BUN (Blood Urea Nitrogen), creatinine, and BUN/creatinine ratios were comparable in groups A and B, increased markedly in group C and significantly lower in group D compared with group C. APAP caused significant centrilobular necrosis and glomerular damage in unsupplemented animals, while NM prevented these alterations. The results indicate that NM has potential to protect against APAP-induced liver and kidney damage.
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PMID:A nutrient mixture prevents acetaminophen hepatic and renal toxicity in ICR mice. 1865 Feb 54

The pathophysiological mechanisms of thioacetamide (TAA)-induced hepatic fibrogenesis are not yet fully understood. In particular, the role of hepatic stellate cells (HSCs) remains unclear. We therefore examined proliferation and transdifferentiation of HSC as well as the underlying molecular mechanisms in TAA-induced fibrosis. Hepatic fibrogenesis was induced in mice by addition of TAA to drinking water. Liver damage was determined by assessment of alanine aminotransferase and aspartate aminotransferase levels, and measurement of collagen deposition. Additionally, expression patterns of alpha-smooth muscle actin, glial fibrillary acidic protein (GFAP, specific hepatic biomarker for HSC), cysteine- and glycine-rich protein 2 (CRP2, specific marker of HSC transdifferentiation), tissue inhibitor of metalloproteinases-1, matrix metalloproteinase-9 (MMP-9), interleukins (IL-1beta, IL-6), platelet-derived growth factors (PDGF-B, PDGF-D) , tumor necrosis factor (TNF)-alpha, and (transforming growth factor (TGF)-beta1 were assessed by real-time PCR. Transcription of GFAP and CRP2 were transiently upregulated during TAA-induced fibrogenesis (punctum maxima (p.m.) week 10 for GFAP and week 14 for CRP2). Similar transient expression patterns were demonstrated for IL-1beta, IL-6, TGF-beta1, and PDGF-B (p.m. week 12) whereas TNF-alpha and PDGF-D continuously increased with ongoing liver injury. In particular, not only neutrophil granulocytes, but also macrophages and leukocytes served as a major source for MMP-9 expression. GFAP and CRP2 expression patterns demonstrated transiently increased HSC-activation during TAA-induced hepatic fibrogenesis. The rate of increase of transcription of GFAP correlated best with PDGF-B, whereas CRP2 levels correlated with PDGF-B, PDGF-D, and IL-1beta expression. This study demonstrates for the first time that transiently increased activation patterns of HSC are observed in toxically induced hepatic fibrosis. Thus, TAA in drinking water is an effective and elegant model to induce reproducible states of liver fibrosis without parenchymal damage in mice.
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PMID:Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice. 1879 50

We examined the effect of taurine depletion on hepatic sulfur-containing amino acid metabolism and carbon tetrachloride-induced acute liver injury. Mice were supplemented with beta-alanine (3%) in drinking water for one week. beta-Alanine intake significantly reduced hepatic taurine levels, but did not influence S-adenosylmethionine, S-adenosylhomocysteine, glutathione levels or methionine adenosyltransferase activity in liver. However, hepatic cysteine levels were significantly elevated by beta-alanine administration. Hepatotoxicity caused by carbon tetrachloride (50 microl/kg, ip) in mice fed beta-alanine was decreased, as determined by changes in serum aspartate aminotransferase, alanine aminotransferase and sorbitol dehydrogenase activities. Hepatic glutathione and taurine levels after a carbon tetrachloride challenge were markedly increased by beta-alanine exposure. The results suggest that enhanced availability of cysteine for synthesis of glutathione and/or taurine may account for the hepatoprotective effects of beta-alanine against carbon tetrachloride-induced acute liver injury.
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PMID:Taurine depletion by beta-alanine inhibits induction of hepatotoxicity in mice treated acutely with carbon tetrachloride. 1923 61

Acetaminophen (APAP) is safe at therapeutic levels but causes hepatotoxicity via N-acetyl-p-benzoquinone imine-induced oxidative stress upon overdose. To determine the effect of human (h) pregnane X receptor (PXR) activation and CYP3A4 induction on APAP-induced hepatotoxicity, mice humanized for PXR and CYP3A4 (TgCYP3A4/hPXR) were treated with APAP and rifampicin. Human PXR activation and CYP3A4 induction enhanced APAP-induced hepatotoxicity as revealed by hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities elevated in serum, and hepatic necrosis after coadministration of rifampicin and APAP, compared with APAP administration alone. In contrast, hPXR mice, wild-type mice, and Pxr-null mice exhibited significantly lower ALT/AST levels compared with TgCYP3A4/hPXR mice after APAP administration. Toxicity was coincident with depletion of hepatic glutathione and increased production of hydrogen peroxide, suggesting increased oxidative stress upon hPXR activation. Moreover, mRNA analysis demonstrated that CYP3A4 and other PXR target genes were significantly induced by rifampicin treatment. Urinary metabolomic analysis indicated that cysteine-APAP and its metabolite S-(5-acetylamino-2-hydroxyphenyl)mercaptopyruvic acid were the major contributors to the toxic phenotype. Quantification of plasma APAP metabolites indicated that the APAP dimer formed coincident with increased oxidative stress. In addition, serum metabolomics revealed reduction of lysophosphatidylcholine in the APAP-treated groups. These findings demonstrated that human PXR is involved in regulation of APAP-induced toxicity through CYP3A4-mediated hepatic metabolism of APAP in the presence of PXR ligands.
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PMID:Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity. 1946 Sep 45


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