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 functional efficacies of inhibitors of L-glutamate uptake for altering second messenger formation in baby hamster kidney cells expressing subtypes mGluR1a, mGluR2, and mGluR4 of the metabotropic glutamate receptor family were examined. L-Serine-O-sulfate was an agonist at mGluR1a (EC50 = 70 microM), mGluR2 (EC50 = 25 microM), and mGluR4 (EC50 = 324 microM). L-Cysteine sulfinate, 1-aminocyclobutane-trans-1,3-dicarboxylate, L-cysteine, and DL-threo-3-methylaspartate stimulated phosphoinositide hydrolysis in mGluR1a cells with EC50 values of 43, 64, 463, and 488 microM, respectively, and displaced L-[3H]glutamate binding from membranes prepared from these cells with respective IC50 values of 48, 44, 79, and 139 microM. However, D-aspartate, L-trans-pyrrolidine-2,4-dicarboxylate, L-threo-3-hydroxyaspartate, and L-aspartate-beta-hydroxamate stimulated phosphoinositide hydrolysis in mGluR1a cells (respective EC50 values of 73, 54, 57, and 430 microM) but did not displace L-[3H]glutamate binding. These compounds inhibited Na(+)-dependent L-glutamate uptake into baby hamster kidney cells with IC50 values similar to those for stimulation of phosphoinositide hydrolysis in mGluR1a cells. Phosphoinositide hydrolysis in mGluR1a cells, as stimulated by inhibitors of (or substrates for) this L-glutamate transporter, was significantly attenuated in the presence of L-glutamate decarboxylase (EC 4.1.1.15) or L-alanine aminotransferase (EC 2.6.1.2). Furthermore, incubation with 1 mM L-trans-pyrrolidine-2,4-dicarboxylate for 30 min increased the basal levels of free glutamate (1.5 +/- 0.2 microM) in the assay buffer four- to fivefold as measured by HPLC analysis. Thus, heteroexchange with endogenous L-glutamate may lead to erroneous estimations of the functional efficacies at mGluR1a.
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PMID:L-glutamate uptake inhibitors may stimulate phosphoinositide hydrolysis in baby hamster kidney cells expressing mGluR1a via heteroexchange with L-glutamate without direct activation of mGluR1a. 796 21

We examined the effects on alanine aminotransferase and aspartate aminotransferase of different aminothiols (L-cysteine, D-cysteine, cysteamine, L-cysteine ethyl ester, L-cysteine methyl ester) and several vitamin B-6 derivatives (pyridoxal, pyridoxamine, pyridoxol, pyridoxol 5'-phosphate), before and after treatment with KOCN, which transforms these molecules into the corresponding carbamoyl derivatives. Only GPT, and not GOT, was specifically inhibited by L-cysteine and, to a lesser extent, by D-cysteine. The association reaction: PLP + apo GPT<-->holo GPT was inhibited by the vitamin B-6 derivatives, and this inhibition was prevented by pretreatment of the vitamin B-6 derivatives with KOCN. All the observed effects occurred at pH 7, 37 degrees C, at mM and even lower concentrations of reagents. Hence, they all potentially play a physiological role, in the regulation of the PLP dependent enzymes and of the vitamin B-6 levels in the cell.
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PMID:The regulation of alanine and aspartate aminotransferase by different aminothiols and by vitamin B-6 derivatives. 814 66

Morphological changes in mitochondria are observed early in the course of acetaminophen (AA)-induced hepatotoxicity, and mitochondrial dysfunction has been observed both in vivo and in vitro following exposure to AA. This study examined the early effects of AA exposure in vivo on mitochondrial respiration and evaluated the effectiveness of N-acetyl-L-cysteine (NAC) in protecting against respiratory dysfunction. Mitochondria were isolated from the livers of fasted, male CD-1 mice 0, 0.5, 1, 1.5 or 2 h after administration of a hepatotoxic dose of AA (750 mg/kg). Glutamate- and succinate-supported mitochondrial respiration were subsequently assessed by polarographic measurement of state 3 (ADP-stimulated) and state 4 (resting) rates of oxygen consumption and determination of the corresponding respiratory control ratios (RCR: state 3/state 4) and ADP:O ratios. Hepatotoxicity was assessed histologically and by measuring plasma alanine aminotransferase (ALT) activity. The earliest sign of mitochondrial dysfunction observed in this study was a significant decrease in the ADP:O ratio for the oxidation of glutamate 1 h post-dosing. At 1.5 and 2 h post-dosing the RCRs for both glutamate- and succinate-supported respiration were significantly decreased. All of the respiratory parameters measured in this study were significantly decreased, with the exception of succinate-supported state 4 respiration which was significantly increased, 2 h after AA administration. Thus, inhibition of mitochondrial respiration preceded overt hepatic necrosis, indicated by an elevation of ALT activity, which was not observed until 3 and 4 h post-dosing. In addition, mitochondrial respiratory dysfunction correlated with morphological alterations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity. 817 80

Hepatitis C virus (HCV) is an RNA virus that replicates in both the liver and lymphoid cells. Interferon-alpha (IFN-alpha) is a useful treatment of chronic hepatitis C (CHC) although resistance to this drug occurs frequently. The mechanisms underlying resistance to IFN remain unknown. In this work, we have measured the levels of glutathione in plasma and peripheral lymphoid cells from 15 healthy controls and 24 CHC patients, 10 of whom were without treatment and 14 showed high serum alanine aminotransferase (ALT) values despite therapy with lymphoblastoid IFN for more than 4 months. In all patients, glutathione levels in plasma and in mononuclear cells were depressed in comparison to controls. In IFN-unresponsive patients, the addition of 600 mg tid of oral N-acetyl cysteine (NAC), a glutathione precursor, resulted in a steady decrease of ALT values in all patients, with complete normalization in 41% of cases after 5-6 months of combined therapy. Administration of NAC alone for 1 month was without effect in the 10 patients that were not receiving IFN. Supplementation of IFN with NAC induced a near normalization of intralymphocytic glutathione, but plasma levels were only moderately increased. HCV replication was markedly inhibited in lymphocytes and viremia was cleared in one of the 8 patients tested. In conclusion, NAC enhances the response to IFN in CHC. Controlled studies are needed to ascertain whether antioxidant therapy might act in synergy with IFN in chronic viral hepatitis.
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PMID:N-acetyl cysteine enhances the response to interferon-alpha in chronic hepatitis C: a pilot study. 822 88

A substantial fraction of the cysteine added to total parenteral nutrition (TPN) solutions is converted to the corresponding thiazolidine derivative, while in solution with relatively large concentrations of glucose typical of TPN (700 mM and higher). It was recently reported (Roberts et al. (1987) J. Med. Chem. 30, 1891-1896) that this thiazolidine, D-glucose-L-cysteine (DGC), offered no significant protection against the hepatic injury caused by 5 mmol/kg of acetaminophen in mice, suggesting that the cysteine present as DGC is poorly bioavailable in vivo. In the present study, fasted male ICR mice given 1.6 or 2.6 mmol/kg of acetaminophen sustained hepatic injury, estimated by elevations in plasma alanine aminotransferase (ALT) activities. Administration of 2.5 mmol/kg of N-acetylcysteine (NAC) 1 h before acetaminophen given i.p. prevented the rise in plasma ALT activities, apparently through support of glutathione (GSH) synthesis. Administration of 2.5 mmol/kg of DGC prior to acetaminophen resulted in slightly lower mean plasma ALT activities than were observed in animals given saline before acetaminophen, but the effect was not statistically significant. When DGC was given 1 h before p.o. administration of 1.6 or 2.6 mmol/kg of acetaminophen, the protective effects of DGC were statistically significant (P < 0.01, 0.025, respectively), although NAC afforded significantly greater protection than did DGC at the higher dose of acetaminophen. Given 4 h before acetaminophen, DGC attenuated acetaminophen-induced increases in plasma ALT activities significantly, whereas NAC was without effect. These results indicate that the cysteine in DGC is at least partially bioavailable in vivo and, further, that DGC may function as a slow release formulation of cysteine.
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PMID:Attenuation of acetaminophen hepatotoxicity in mice as evidence for the bioavailability of the cysteine in D-glucose-L-cysteine in vivo. 831 Apr 51

Glutathione (GSH) is the major intracellular antioxidant and is essential to normal cell function and replication. Cysteine and other thiol compounds have been considered rate-limiting for GSH biosynthesis, but recent studies have demonstrated that glutamine (GLN) becomes essential during metabolic stress to replete tissue GSH levels which have become depleted. To determine the role of GLN supplementation in the resting, nonstressed state, we studied three groups of Wistar rats. The animals were catheterized and randomly assigned to one of three groups; (1) chow ad libitum group receiving iv saline (control), (2) standard total parenteral nutrition (STA-TPN) group, and (3) glutamine-enriched TPN (GLN-TPN) group. The intravenously fed animals received no rat chow. The infusions were administered at a rate of 2.2 ml/hr for 4 days and all animals were harvested on the fifth day of study. The GLN-TPN group had a significantly higher plasma GSH level than STA-TPN or control animals (P < 0.01). The hepatic concentration of GSH and the oxidized GSH/reduced GSH were similar in all groups. GLN-TPN had a significantly lower plasma ALT level than the control group (P < 0.05). The control group had a significantly higher ALP level than STA-TPN and GLN-TPN animals (P < 0.01). There were no significant differences in other measures of hepatic functions among the three groups. Our data demonstrate that in this model GLN-enriched TPN enhances plasma GSH concentrations, while maintaining hepatic GSH stores. This suggests that GSH turnover is altered during glutamine-enriched TPN, which may explain how dietary GLN supplementation enhances tissue antioxidant capacity.
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PMID:Glutamine-enriched total parenteral nutrition enhances plasma glutathione in the resting state. 876 39

Metallothioneins (MTs) are low-molecular weight, cysteine-rich, metal-binding proteins. Pretreatment of animals with Zn increases tissue MT concentrations, and protects against Cd-induced toxicity. However, Zn treatment produces many effects in addition to increasing MT. Therefore, MT-I and -II knock-out (MT-null) mice were used to determine the roles of MT in Cd-induced hepatotoxicity and nephrotoxicity, as well as in Zn-induced protection. MT-null mice were more sensitive to CdCl2 (25 mumol/kg i.p.) hepatotoxicity, as evidenced by 25-fold increases in serum alanine aminotransferase activity, compared to 12-fold increases in control mice. Zn pretreatment (200 mumol/kg s.c. x 2 days) increased hepatic MT 80 fold in control mice but not in MT-null mice, and prevented CdCl2 hepatotoxicity in control mice only. It is concluded that MT plays a critical role in Cd-induced hepatotoxicity. In contrast to CdCl2-induced hepatotoxicity, MT-null mice were equally susceptible as controls to the Cd-MT (CdMT) (0.1-0.4 mg Cd/kg i.v.) nephrotoxicity, as evidenced by similar increases in urinary protein (up to 30-fold) and glucose excretion (up to 60-fold), as well as similar extent of proximal tubular necrosis. Zn increased renal MT (28-fold) in control mice only; however, it protected against CdMT-induced renal injury in both control and MT-null mice. These findings suggest that MT plays less of a protective role in protecting against CdMT-induced nephrotoxicity than CdCl2-induced hepatotoxicity, and that Zn-induced protection against CdMT-induced nephrotoxicity does not appear to be mediated through MT.
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PMID:Metallothionein plays less of a protective role in cadmium-metallothionein-induced nephrotoxicity than in cadmium chloride-induced hepatotoxicity. 878 54

Incubation of pig heart cytosolic aspartate aminotransferase (pyridoxal 5'-phosphate form) with 10 mM 2-oxoglutaconic acid dimethyl ester for 2 h at 25 degrees C (pH 7.0) results in slight inactivation (approximately 15%). However, incubation of the enzyme with glutamate, or prior conversion of the enzyme to the pyridoxamine 5'-phosphate form, results in more extensive inactivation. The inactivation of the enzyme by 2-oxoglutaconic acid dimethyl ester is most pronounced in the presence of both glutamate and alpha-ketoglutarate. N-Ethylmaleimide was previously shown to alkylate two surface cysteine residues (I and II) and to react syncatalytically with a third cysteine residue (III) of cytosolic pig heart aspartate aminotransferase [Birchmeier et al. (1973) J. Biol. Chem. 248, 1751-1759]. Alkylation of cysteine III results in inactivation of the enzyme, despite the fact that this residue is not essential for catalysis. The present results suggest that 2-oxoglutaconic acid dimethyl ester reacts with the enzyme in a similar fashion to that exhibited by N-ethylmaleimide. Some inactivation by alkylation of a susceptible group at the active site cannot be ruled out. However, the rate of inactivation of cytosolic pig heart aspartate aminotransferase is proportional to the concentration of 2-oxoglutaconic acid dimethyl ester up to a concentration of at least 40 mM, suggesting that the compound binds very poorly to the active site or that alkylation at the active site is slow compared with syncatalytic alkylation of cysteine III. The t 1/2 for inactivation of pig heart cytosolic aspartate aminotransferase by 40 mM 2-oxoglutaconic acid dimethyl ester (in the presence of 10 mM L-glutamate, pH 7.2, 25 degrees C) is 9 min. Incubation of cytosolic pig heart aspartate aminotransferase with 10 mM 2-oxoglutaconate for 2 h (25 degrees C, pH 7.2) results in significant inactivation (approximately 30%). The enzyme is protected against inactivation by the presence of alpha-ketoglutarate, but glutamate enhances the inactivation. These findings suggest that 2-oxoglutaconate is an active site-directed inhibitor. The binding of 2-oxoglutaconate to the enzyme exhibits saturation kinetics (K1 approximately 2 mM), but the rate of inactivation is slow (limiting rate constant for inactivation in the presence of L-glutamate approximately 0.01 min-1; pH 6.0, 25 degrees C; t 1/2 max approximately 70 min). This finding suggests that 2-oxoglutaconate does not readily react in a syncatalytic fashion with cysteine III. Possibly, the two negative charges of 2-oxoglutaconate do not allow ready approach to cysteine III. Rather, the findings suggest that 2-oxoglutaconate binds at the active site of the pyridoxal 5'-phosphate form of the enzyme as an affinity labeling reagent. However, the increased rate of 2-oxoglutaconate-induced inactivation in the presence of glutamate suggests that this unsaturated alpha-keto acid also exhibits the properties of a kcat inhibitor. 2-Oxoglutaconate inactivates aspartate aminotransferase in cytosolic and mitochondrial fractions of rat kidney and purified pig heart alanine aminotransferase. Injection of 2-oxoglutaconate into mice results in inhibition of kidney aspartate aminotransferase. 2-Oxoglutaconate is a substrate of glutamate dehydrogenase. The kinetic constants are similar to those obtained with alpha-ketoglutarate. The results suggest that unsaturated alpha-keto acids and their esters may be useful probes for the study of alpha-keto acid-utilizing enzymes.
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PMID:Irreversible inactivation of aspartate aminotransferase by 2-oxoglutaconic acid and its dimethyl ester. 890 17

Hepatobiliary dysfunction occurs commonly in infants on prolonged parenteral nutrition alimentation; however, the underlying mechanisms causing liver injury are poorly understood. We postulated that oxidant stress played a significant role in parenteral nutrition-induced liver abnormalities and tested this hypothesis in a rat model. Weanling male rats received 8 days of total parenteral nutrition (TPN) through a central venous catheter (TPN group), pair feeding of rat chow and placement of a central venous catheter (sham group), or ad libitum feedings of rat chow (control group). After 8 days of TPN, serum alanine aminotransferase and cholylglycine levels were elevated, hepatocellular steatosis was present, hepatic mitochondria had dilated intracristal spaces, and lipid peroxidation of mitochondria was increased compared with sham and control groups. Hepatic glutathione levels decreased to 16% of control values after 5 days of TPN; this was followed by mitochondrial lipid peroxidation and elevated serum cholylglycine levels after 8 days of TPN. Sham and control rats showed no evidence of mitochondrial lipid peroxidation or liver injury after 8 days. Removal of metabisulfate from TPN solutions and addition of cysteine HCl or choline had no major effect on these findings. Bacterial translocation was not increased in TPN rats. These data suggest that glutathione depletion and oxidant stress are important factors in the pathogenesis of TPN-induced liver abnormalities in the weanling rats.
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PMID:Hepatic oxidant injury and glutathione depletion during total parenteral nutrition in weanling rats. 892

The C-S lysis of L-cysteine conjugates is one biotransformation pathway which is responsible for the generation of mutagenic and cytotoxic metabolic species. Thirteen cysteine S-conjugates were synthesized in our laboratories and incubated with aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) enzymes from porcine heart tissue. The C-S lyase (CSL) activity for each enzyme-substrate combination was determined. ASAT and ALAT were shown to exhibit CSL activity and it was also demonstrated that this activity was inhibited in the presence of the pyridoxal phosphate-dependent enzyme inhibitor amino(oxyacetic acid) confirming the pyridoxal phosphate-dependent mechanism by which C-S lysis is known to take place. This finding has potentially important implications for the risk assessment of compounds which produce L-cysteine conjugates during their biotransformation.
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PMID:Novel sources of mammalian C-S lyase activity. 893 63


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