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

---

Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One hundred cases of severe paracetamol poisoning were treated with intravenous N-acetylcysteine (acetyl-cysteine). There was virtually complete protection against liver damage in 40 patients treated within eight hours after ingestion (mean maximum serum alanine transaminase activity 27 IU/1). Only one out of 62 patients treated within 10 hours developed severe liver damage compared with 33 out of 57 patients (58%) studied retrospectively who received supportive treatment alone. Early treatment and acetylcysteine also prevented renal impairment and death. The critical ingestion-treatment interval for complete protection against severe liver damage was eight hours. Efficacy diminished progressively thereafter, and treatment after 15 hours was completely ineffective. Intravenous acetylcysteine was more effective than cysteamine and methionine and noticeably free of adverse effects. It is the treatment of choice for paracetamol poisoning.
...
PMID:Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. 51 12

We have studied the effects of the immunomodulator drug lobenzarit in the model of acute hepatotoxicity induced by a high oral dose (600 mg/kg) of acetaminophen in mice. Lobenzarit at doses of 25, 50 and 100 mg/kg i.p. decreased significantly the activity of alanine aminotransferase in serum, which was increased by acetaminophen alone, and increased the concentration of reduced glutathione in mice liver, which is depleted by acetaminophen. Lobenzarit also reduced liver damage induced by acetaminophen in mice, which was observed by electron microscopy. The hepatoprotective effects of lobenzarit were dose-dependent and they were produced when lobenzarit was administered 30 min before acetaminophen or 2 and 4 h after it. It is concluded that lobenzarit exerts some effects which resemble those of an antidote of acetaminophen such as N-acetylcysteine.
...
PMID:Hepatoprotective effects of lobenzarit disodium on acetaminophen-induced liver damage in mice. 145 72

N-Acetylcysteine (NAC) is protective against acetaminophen-induced hepatotoxicity primarily by providing precursor for the glutathione synthetase pathway, while cysteamine has been demonstrated to alter the cytochrome P-450 dependent formation of toxic acetaminophen metabolite. Mice administered acetaminophen (500 mg/kg) had elevations of serum alanine aminotransferase (ALT) to 273.0 +/- 37.5 and 555.8 +/- 193.4 U/mL at 12 and 24 h, respectively, after injection. Administration of cysteamine (100 mg/kg) or NAC (500 mg/kg) significantly reduced serum ALT activity (p less than 0.001). Reducing the dose of NAC or cysteamine by 50% greatly reduced their hepatoprotective effect while the co-administration of the reduced doses of NAC (250 mg/kg) and cysteamine (50 mg/kg) following acetaminophen overdose prevented elevation of serum ALT activity (39.2 +/- 1.17 and 32.5 +/- 5.63 U/mL at 12 and 24 h post-injection, p less than 0.001) and preserved normal mouse hepatic histology. Neither NAC (500 mg/kg), cysteamine (100 mg/kg), or the lower doses in combination of both agents were found to alter the half-life or peak levels of acetaminophen. Liver microsomal aryl hydrocarbon hydroxylase activity measured 24 h after drug administration was not significantly different between treatment groups and controls receiving only saline. These results indicate a possible role for the concomitant use of NAC and cysteamine in the prevention of hepatic necrosis following toxic doses of acetaminophen. Neither decrease in plasma acetaminophen levels nor depression of cytochrome P-450 enzyme activity appears to be the mechanism of protection when these doses of NAC, cysteamine, or both drugs together are administered with a toxic dose of acetaminophen in mice.
...
PMID:Cysteamine in combination with N-acetylcysteine prevents acetaminophen-induced hepatotoxicity. 158 51

Acute 1,2-dichloropropane (DCP) poisoning in humans is relatively frequent in Italy, where DCP is widely diffused as a constituent of commercial solvents and dry cleaners. In this study we have investigated the effects of DCP on intracellular glutathione (GSH) content in main target tissues of male Wistar rats, i.e. liver, kidney and blood, in order to establish if a correlation between DCP-induced GSH depletion and tissue damage exists. Administration of DCP (2 ml/kg body weight orally) caused a dramatic loss of tissue GSH occurring 24 h after DCP intoxication, followed by a slow restoration approaching physiological levels after 96 h. GSH depletion was associated with a marked increase in serum GOT, GPT, 5'-nucleotidase, gamma-glutamyl transpeptidase, alkaline phosphatase, urea and creatinine, and a significant degree of hemolysis. When animals were pretreated with a GSH depleting agent, buthionine-sulfoximine (BSO) (0.5 g/kg body weight) i.p. 4 h before DCP intoxication, an increase of overall mortality was found, significantly different from the group of animals treated with DCP alone. On the contrary, the administration of a GSH precursor, N-acetylcysteine (NAC) i.p. (250 mg/kg body weight) 2 and 16 h after DCCP intoxication prevented the dramatic loss of cellular GSH and reduced the extent of injury in target tissues, as demonstrated by laboratory indices. Furthermore, statistical analysis of the data revealed a correlation between: (1) depletion of liver GSH and increase in serum GOT, GPT, 5'-nucleotidase, (2) depletion of kidney GSH and increase in serum urea and creatinine and (3) depletion of blood GSH and the occurrence of hemolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:1,2-Dichloropropane (DCP) toxicity is correlated with DCP-induced glutathione (GSH) depletion and is modulated by factors affecting intracellular GSH. 198 Apr 7

Concentrations of glutathione S-transferase (GST; glutathione transferase; EC 2.5.1.18) B1 subunits, F protein, and the activity of alanine aminotransferase (ALT; EC 2.6.1.2) were measured in sequential plasma samples taken from nine patients with self-administered paracetamol (acetaminophen) poisoning. GST exceeded the reference interval in all patients at the time of admission, and F protein was increased in seven. In contrast, abnormal activities of ALT in plasma were found in only one of the nine on admission, a patient admitted 12 h after poisoning. Subsequent to admission nine, eight, and five patients, respectively, had abnormal concentrations of GST, F protein, and ALT. When expressed as multiples of the upper reference limit, the highest values for GST measured in each patient always far exceeded the greatest abnormalities in ALT; this was true for F protein in only five patients. Patients in whom the concentration of GST exceeded 10 micrograms/L on admission subsequently went on to develop moderate or severe liver damage, despite treatment with N-acetylcysteine. F protein and ALT measurements on admission were not as efficient as GST at predicting the clinical outcome of the patients. We conclude that GST and F protein offer clear advantages over ALT for detecting minor degrees of acute liver dysfunction, particularly when only centrilobular damage may be involved.
...
PMID:Plasma glutathione S-transferase and F protein are more sensitive than alanine aminotransferase as markers of paracetamol (acetaminophen)-induced liver damage. 258 14

Seventeen patients received standard treatment with intravenous N-acetylcysteine for 18 episodes of severe poisoning with paracetamol (acetaminophen). The dose of N-acetylcysteine was 150 mg/kg given in 15 min followed by 50 mg/kg in 4 h and 100 mg/kg over the next 16 h. Liver damage was absent or mild on 13 occasions (ALT greater than 500 mu/l) and severe on 5 (ALT less than 1000 mu/l). Total plasma N-acetylcysteine was estimated by HPLC. The mean maximum plasma concentration after the initial loading dose was 554 mg/l. Concentrations then fell rapidly and after 12 h a mean steady-state level of about 35 mg/l was maintained. When the infusion was discontinued N-acetylcysteine disappeared with a half-life of 5.7 h. The mean steady-state volume of distribution, AUC, mean residence time and total clearance were 536 ml/kg, 1748 mg.h.l-1, 2.91 h and 3.18 ml.min-1.kg-1. These values are generally consistent with those previously reported with much smaller doses and the disposition of N-acetylcysteine does not appear to be dose-dependent. The elimination of N-acetylcysteine was not impaired in the patients with severe liver damage, and the pharmacokinetic variables and plasma concentrations were similar in patients with and without hepatotoxicity. The dosage schedule for intravenous N-acetylcysteine should probably be modified since adverse reactions invariably occur early when plasma concentrations are at their highest, and liver damage was prevented just as effectively at the lowest as at the highest Cmax. High initial concentrations of N-acetylcysteine can be avoided with simple alternative regimens based on the kinetic data of this study.
...
PMID:The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage. 259 89

Mice poisoned with acetaminophen were treated with esterase inhibitors, buthionine sulfoximine, and N-acetyl-L-lysine in experiments designed to explore the mechanism of N-acetylcysteine protection in vivo. Three esterase inhibitors, phenylmethylsulfonyl fluoride, bis-(p-nitrophenyl)-phosphate, and diisopropylfluorophosphate, had no effect on the antidote effectiveness of N-acetylcysteine, although each provided partial protection against acetaminophen poisoning. Buthionine sulfoximine, a specific inhibitor of gamma-glutamyl cysteine synthetase, antagonized the antidote effect of N-acetylcysteine. Acetaminophen-induced hepatotoxicity, as measured by plasma alanine aminotransferase activity, and mortality failed to decline, consistent with stimulation of glutathione synthesis as the primary mechanism of antidote protection. N-Acetyl-L-lysine was given at doses up to ten-fold higher than N-acetylcysteine yet had no effect on acetaminophen hepatotoxicity or its prevention by N-acetylcysteine. These results advance the view that N-acetylcysteine acts primarily as a glutathione precursor. They further suggest the esterase inhibitors limit poisoning by acetaminophen and may be useful agents in antagonizing the toxicity of other metabolically activated drugs.
...
PMID:Effects of esterase inhibitors and buthionine sulfoximine on the prevention of acetaminophen hepatotoxicity by N-acetylcysteine. 310 95

Acetaminophen can be enzymatically bioactivated, which may play a role in cataractogenesis. This study evaluated the relation of dose, sex, plasma drug concentration, cytochromes P-450 (P-450 and P-448) induction, and hepatocellular toxicity to cataractogenic susceptibility in inbred mice and rabbits. C57BL/6 or DBA/2 mice, which respectively are genetically responsive and nonresponsive to P-448 induction, were treated with acetaminophen, 300 to 1000 mg/kg intraperitoneally (ip), following pretreatment with the P-448 inducer 3-methylcholanthrene (3-MC). Bilateral cataracts developed, independent of sex, in 83% of C57BL/6 mice within 4 hr of acetaminophen administration, compared with 7% of DBA/2 mice. A dose-response relation for cataractogenesis was evident in C57BL/6 mice using doses of 300 and 400 mg/kg, with the higher dose producing similar plasma acetaminophen concentrations but twofold higher glucuronide concentrations. Both strains had increased plasma concentrations of glutamic-pyruvic transaminase (GPT). New Zealand white or Chinchilla pigmented rabbits were treated with single or multiple doses of acetaminophen, 500 to 1500 mg/kg/day ip, following pretreatment with a cytochromes P-450 inducer: phenobarbital, 3-MC, or beta-naphthoflavone. Acetaminophen given chronically caused lenticular opacities within 1 week in 19 of 20 rabbits pretreated with P-450 inducers, regardless of pigmentation, but not in animals without prior P-450 induction. No opacities were observed after a single dose of acetaminophen, even with P-450 induction. There was no increase in plasma GPT in rabbits with any treatment. Over 85% of acetaminophen was recovered in urine as a glucuronide conjugate, and the rest as acetaminophen or conjugates with sulfate, cysteine, or N-acetylcysteine. Susceptibility to acetaminophen cataractogenesis can be genetically predetermined and may involve enzymatic bioactivation. possibly independent of hepatic biotransformation and toxicity.
...
PMID:Pharmacological studies on the in vivo cataractogenicity of acetaminophen in mice and rabbits. 339 87

We have reported previously that methoxsalen is a suicide substrate for cytochrome P-450. We now report its effects on the metabolism and toxicity of acetaminophen in mice. Intragastric administration of methoxsalen (125 mumol X kg-1), 30 min before that of acetaminophen (600 mg X kg-1 i.p.), decreased the formation of the mercapturate and cysteine conjugates of acetaminophen, the depletion of glutathione and the in vivo covalent binding of an acetaminophen metabolite to hepatic proteins and prevented the increase in serum glutamic-pyruvic transaminase activity, the appearance of liver lesions and mortality. Methoxsalen (250 mumol X kg-1) also afforded complete protection when given intragastrically 2 hr after acetaminophen (600 mg X kg-1 i.p.). At that time, methoxsalen still decreased in vivo covalent binding measured per whole liver, and permitted a faster recovery of hepatic glutathione. Methoxsalen (180 mumol X kg-1) and N-acetylcysteine (919 mumol X kg-1) exerted additive protective effects when given concomitantly 2 hr after acetaminophen. We conclude that administration of methoxsalen decreases the metabolic activation and the hepatotoxicity of acetaminophen in mice.
...
PMID:Pre- or post-treatment with methoxsalen prevents the hepatotoxicity of acetaminophen in mice. 377 10

Exposure of hyperthyroid rats to halothane results in a centrilobular necrosis of the liver and an 11-fold increase in serum glutamate-pyruvate transaminase (SGPT) levels. These effects are not seen in euthyroid animals. Paradoxically, administration of diethylmaleate to hyperthyroid rats significantly decreased the levels of hepatic glutathione and blocked the halothane-induced hepatic necrosis as well as decreased the elevation of SGPT. In contrast, pretreatment of animals with N-acetylcysteine, an intracellular sulfhydryl repletor , significantly increased the severity of the halothane-induced hepatic necrosis and increased the elevation of SGPT. Similarly, cysteamine, another intracellular sulfhydryl repletor , also exacerbated halothane-induced liver injury. Halothane-induced hepatotoxicity is at least in part apparently regulated by cellular glutathione levels. Paradoxically, glutathione seems to be involved in the bioactivation rather than the detoxification of halothane.
...
PMID:Paradoxical effects of perturbation of intracellular levels of glutathione on halothane-induced hepatotoxicity in hyperthyroid rats. 672 95


1 2 3 4 5 6 7 8 9 10 Next >>

---