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)

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that causes massive centrilobular hepatic necrosis at high doses, leading to death. The objectives of this study were to test our working hypothesis that preplaced cell division and hepatic tissue repair by prior thioacetamide (TA) administration provides protection against APAP-induced lethality and to investigate the underlying mechanism. Male Sprague-Dawley rats were treated with a low dose of TA (50 mg/kg, intraperitoneally [i.p.]) before challenge with a 90% lethal dose (1,800 mg/kg, i.p.) of APAP. This protocol resulted in a 100% protection against the lethal effect of APAP. Because TA caused a 23% decrease of hepatic microsomal cytochromes P-450, the possibility that TA protection may be caused by decreased bioactivation of APAP was examined. A 30% decrease in cytochromes P-450 induced by cobalt chloride failed to provide protection against APAP lethality. Time course of serum enzyme elevations (alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase) indicated that actual infliction of liver injury by APAP peaked between 12 to 24 hours after the administration of APAP, whereas the ultimate outcome of that injury depended on the biological events thereafter. Although liver injury progressed in rats receiving only APAP, it regressed in rats pretreated with TA. Acetaminophen t1/2 was not altered in TA-treated rats, indicating that significant changes in APAP disposition and bioactivation are unlikely. Moreover, hepatic glutathione was decreased to a similar extent regardless of TA pretreatment, suggesting that decreased bioactivation of APAP is unlikely to be the mechanism underlying TA protection. [3H]Thymidine incorporation studies confirmed the expected stimulation of S-phase synthesis, and proliferating cell nuclear antigen studies showed a corresponding stimulation of cell division through accelerated cell cycle progression. Intervention with TA-induced cell division by colchicine antimitosis ended the TA protection in the absence of significant changes in the time course of serum enzyme elevations during the inflictive phase of APAP hepatotoxicity. These studies suggest that hepatocyte division and tissue repair induced by TA facilitate sustained hepatic tissue repair after subsequent APAP-induced liver injury, producing recovery from liver injury and protection against APAP lethality.
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PMID:Stimulated hepatic tissue repair underlies heteroprotection by thioacetamide against acetaminophen-induced lethality. 784 22

Paracetamol (acetaminophen) 90-150 mg.kg-1 increased the activity of serum glutathione S-transferase (GST) and yet reduced the activities of liver microsomal and homogenate GST in mice. The GST activity was dose- and time-related to paracetamol. A negative correlation was found between serum GST and liver homogenate GST, as well as between serum GST and liver microsomal GST. A good positive correlation between serum GST and serum alanine aminotransferase (AAT) was also seen. In addition, butylated hydroxyanisole (BHA) and sodium ferulate (SF) remarkably reversed the changes of serum GST and serum AAT activities in paracetamol-treated mice. These results suggested that the conjugation level in liver was decreased in paracetamol-induced hepatotoxicity in mice.
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PMID:[Effects of paracetamol on glutathione S-transferase activity in mice]. 801 73

1. Hepatoprotective activity of hydro-methanolic extract of Artemisia scoparia (Compositae) was investigated against acetaminophen-induced hepatic damage. 2. Acetaminophen at a dose of 1 g/kg produced 100% mortality in mice while pretreatment of animals with plant extract (150 mg/kg) reduced the death rate to 20%. 3. Acetaminophen at a dose of 640 mg/kg produced liver damage in rats as manifested by the rise in serum levels of GOT and GPT to 1528 +/- 310 and 904 +/- 261 IU/l (n = 10) respectively, compared to respective control values of 80 +/- 11 and 38 +/- 09. 4. Pretreatment of rats with plant extract (150 mg/kg) lowered significantly the respective serum GOT and GPT levels to 85 +/- 11 and 23 +/- 06. 5. These results indicate that Artemisia scoparia contains hepatoprotective constituents and this study rationalizes the traditional use of this plant in hepatobiliary disorders.
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PMID:Protective effect of Artemisia scoparia extract against acetaminophen-induced hepatotoxicity. 811 19

The hepatoprotective effects of misoprostol on acetaminophen (APAP)-induced toxicity were studied in the rat. Liver injury was evaluated at 36 hr after APAP administration by measuring serum ornithine carbamoyltransferase (OCT) and alanine aminotransferase (ALT) levels, by using tetranitroblue tetrazolium (TNBT) staining and by histological analysis. After APAP administration, peak serum levels of the drug were detected at 15 min. Liver GSH was depleted from control levels of 448 +/- 48 micrograms/g to 82 +/- 2 micrograms/g (P < 0.01) within 3 hr. Serum ALT levels increased significantly after 16 hr and H&E staining revealed significant hepatic necrosis after 12 hr. Rats treated with misoprostol before and after APAP administration showed reduced OCT and ALT levels at 36 hr of overdose (454 +/- 446 IU/liter and 2571 +/- 2944 IU/liter, respectively) compared to those without misoprostol treatment (1348 +/- 480 IU/liter and 6077 +/- 3025 IU/liter, respectively, P < 0.01). TNBT staining showed a reduced area of damage from 28.6 +/- 22.3% to 7.3 +/- 8.9% (P < 0.01), and H&E staining also showed less extensive hepatic necrosis in rats treated with misoprostol before and after the overdose. In a time sequence study, misoprostol treatment starting within 10 hr of overdose showed the same protective effect as when it was given before and after APAP ingestion. No protection was detected when the treatment was started during the development of hepatic injury. However, misoprostol given when injury was established seemed to be protective. Our results show that misoprostol protects the liver against APAP-induced injury if given within 10 hr of overdose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Misoprostol protection against acetaminophen-induced hepatotoxicity in the rat. 820 Feb 57

A 250 mg/kg subcutaneous injection of acetaminophen (APAP) given to fasted mice was hepatotoxic as indicated by elevated serum alanine aminotransferase activity and electron microscopic studies. When extramitochondrial Ca2+ levels were 200 nM or greater, the APAP caused loss of mitochondrial Ca2+ homeostasis in a two step process that represents a sequence of events. The first step occurs 0 to 3 hours after APAP administration and the second step occurs 6 to 12 hours after APAP administration. Loss of mitochondrial Ca2+ homeostasis 6 to 12 hours after APAP correlates chronologically with nuclear damage as indicated by loss of nuclear Ca2+ sequestration between 6 and 12 hours after APAP administration. Pretreatment of mice with the phospholipase A2 (PLA2) inhibitors chlorpromazine or diltiazem one hour prior to APAP administration inhibits loss of mitochondrial Ca2+ homeostasis, prevents nuclear damage, and inhibits APAP hepatotoxicity as indicated by serum alanine aminotransferase activity and electron microscopic studies. This protective effect of chlorpromazine and diltiazem does not interfer with initial actions of APAP that influence mitochondrial function, but interfers with the sequence of events initiated by APAP that leads to loss of mitochondrial Ca2+ homeostasis and hepatotoxicity.
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PMID:Antagonism of acetaminophen hepatotoxicity by phospholipase A2 inhibitors. 843 30

Ca2+ accumulates in the nucleus and DNA undergoes enzymatic cleavage into internucleosome-length fragments before acetaminophen and dimethylnitrosamine produce hepatic necrosis in vivo and toxic cell death in vitro. However, Ca(2+)-endonuclease fragmentation of DNA is characteristic of apoptosis, a type of cell death considered biochemically and functionally distinct from toxic cell death. The present studies investigate DNA fragmentation as a critical event in toxic cell death by testing whether the Ca(2+)-calmodulin antagonist chlorpromazine and the Ca2+ channel blocker verapamil prevent acetaminophen-induced hepatic necrosis by inhibiting Ca2+ deregulation and DNA damage. Acetaminophen overdose in mice produced accumulation of Ca2+ in the nucleus (358% of control) and fragmentation of DNA (250% of control) by 6 h, with peak release of ALT occurring at 12-24 h (38,000 U/l). Pretreatment with chlorpromazine prevented increases in nuclear Ca2+ and DNA fragmentation and nearly abolished biochemical evidence of toxic cell death. Verapamil pretreatment also decreased Ca2+ accumulation and DNA damage while attenuating liver injury. The Ca2+ antagonists did not protect against toxic cell death through hypothermia because neither produced the delay in toxicity that is customarily associated with hypothermia. Nor did chlorpromazine or verapamil protect through inhibiting acetaminophen bioactivation. Chlorpromazine failed to diminish glutathione depletion in whole liver and isolated nuclei. Verapamil (250 microM) also failed to alter glutathione depletion in whole liver and had no effect on acetaminophen-glutathione adduct formation by mouse liver microsomes and by cultured mouse hepatocytes. Collectively, these results support the hypothesis that Ca(2+)-induced DNA fragmentation plays a significant role in cell necrosis produced by acetaminophen and may contribute to toxic cell death caused by other alkylating hepatotoxins.
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PMID:Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. 846 87

We have investigated the relationship between ATP levels and the onset and progression of cell injury induced by paracetamol overdose both in vivo and in vitro. Liver slices obtained from phenobarbitone-induced and non-induced rats were used in a model in vitro system. Slices were exposed to paracetamol (2-10 mM), for 120 min and then incubated without paracetamol for a further 240 min. ATP levels are reduced upon exposure to paracetamol in liver slices from both phenobarbitone-induced and non-induced rats. Cell injury, as quantified by measuring leakage of lactate dehydrogenase (LDH) and potassium (K+), does not become apparent until 240 min, some 120 min after exposure to paracetamol had ended. This irreversible cell injury is not observed in liver slices from non-induced rats. For in vivo studies rats were phenobarbitone-induced and received i.p. injections of 800 mg/kg body weight paracetamol. Hepatic ATP levels were measured and are found to drop sharply by 3 h post-injection. Development of irreversible hepatic cell injury was assessed by measuring serum enzyme (ALT) activity. ALT levels do not rise until 12 h have elapsed. Paracetamol in overdose gives rise to ATP depletion in liver cells, that is early, independent of paracetamol metabolism and probably spread throughout the lobule. In contrast cell injury is found late and only in our phenobarbitone-induced rats. No cell injury is observed in liver slices from non-induced rats. This suggests that while the level of ATP depletion which is observed may be a necessary part of cell injury by paracetamol, it is not a sufficient cause.
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PMID:Adenosine triphosphate (ATP) levels in paracetamol-induced cell injury in the rat in vivo and in vitro. 856 May 7

Acetaminophen high doses toxicity has been reported in clinical and experimental studies in relation with cytochrome P-450. (Acetaminophen metabolite). Thinking that biliary tract obstructions hould increases drugs toxicity because interferes toxic substances excretion or it modify the activity of P-450 we decided to study acetaminophen toxicity in rats with biliary tract obstruction. Male sprague Dawley rats were used (body weight 250-400 gr) in two groups: Group I control (6 rats) with choledoco bile duct ligated; two doses of saline solution 0.9% Intraperitoneal, 0.2 ml/100 gr. were administrated. Group II (Same surgical intervention) received two doses of acetaminophen (intraperitoneal) solution (400 mg/Kg). This group was divided in two (6 rats each), one of this was sacrificed at 48 h. and the other one at 120 h. after acetaminophen injection. Total, direct and indirect bilirubin, alkaline phosphatase, ALT and AST transaminases, hematology study, liver weight, histological studies of liver and kidney were performed in all rats. High incidence of liver necrosis ans significative transaminases increases were found in group II. Our results were discussed taking account that recent biliary tract obstruction increase acetaminophen toxicity, at a half doses reported in other studies. It is possible that mixed oxidation system activity of cytochrome P-450 was increased in our research.
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PMID:[Effects of cholestasis on hepatotoxicity of acetaminophen in rats]. 856 72

The hepatotoxicity of acetaminophen is believed to be mediated by the reactive metabolite N-acetyl-p-benzoquinone imine; however, the mechanism by which this metabolite produces the toxicity is unknown. The metabolite, which is both an electrophile and an oxidizing agent, may covalently bind to critical proteins, or it may initiate oxidative damage. We have previously developed a Western blot assay for detection of acetaminophen covalently bound to protein and have reported the relationship between covalent binding and the development of hepatotoxicity. Recently, we developed a Western blot assay for protein aldehyde formation, which may occur via the reactive oxygen species, the hydroxyl radical. In this paper, we have compared covalent binding to protein aldehyde formation. Toxic doses of acetaminophen (400 mg/kg) were administered to mice, and the mice were subsequently killed at 0, 1, 2, 4, and 6 h. Since the oxidizing agent FeSO4 has been reported to potentiate lipid peroxidation when administered with acetaminophen, other mice received FeSO4 (100 mg/kg) plus acetaminophen. Compared to saline-treated control mice, acetaminophen treatment significantly increased serum alanine aminotransferase levels, an index of hepatotoxicity, at 4 and 6 h, but not at 1 or 2 h. Acetaminophen plus FeSO4 treatment of mice significantly increased serum alanine aminotransferase levels at 2, 4, and 6 h compared to controls. Levels of alanine aminotransferase in serum of acetaminophen plus ferrous sulfate-treated mice were higher at 4 and 6 h than those of acetaminophen-treated mice, but not significantly different. FeSO4 alone did not increase alanine aminotransferase levels. Western blot assays revealed that acetaminophen did not cause an increase in protein aldehydes over control at any time, nor did acetaminophen plus FeSO4; however, FeSO4 alone increased the intensity of staining of the immunoblot for protein aldehydes over control at all times after 0 time. Acetaminophen-protein adducts were detected in acetaminophen- and acetaminophen plus FeSO4-treated mice. In vitro experiments indicated that FeSO4 plus tert-butyl hydroperoxide in the presence of bovine serum albumin increased protein aldehyde formation. Inclusion of acetaminophen in the incubation mixture inhibited protein oxidation of bovine serum albumin in a concentration dependent manner. The data indicate that acetaminophen quenches protein oxidation, presumably by reacting with the hydroxyl radical. These data are consistent with the theory that acetaminophen covalent binding is the primary mechanism of toxicity and argue against a role for protein oxidation in acetaminophen hepatotoxicity.
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PMID:Mechanism of acetaminophen-induced hepatotoxicity: covalent binding versus oxidative stress. 872 1

Acetaminophen (APAP) produces sex-dependent nephrotoxicity and hepatotoxicity in young adult Sprague-Dawley (SD) rats and age-dependent toxicity in male rats. There is no information regarding the susceptibility of aging female SD rats to APAP toxicity. Therefore, the present studies were designed to determine if sex-dependent differences in APAP toxicity persist in aging rats and to elucidate factors contributing to sex- and age-dependent APAP hepatotoxicity and nephrotoxicity. Young adult (3 months old) and aging (18 months old) male and female rats were killed from 2 through 24 hr after receiving APAP (0-1250 mg/kg, ip) containing [ring-14C]APAP. Trunk blood was collected for determination of blood urea nitrogen (BUN) concentration, serum alanine aminotransferase (ALT) activity, and plasma APAP concentration; urine was collected for determination of glucose and protein excretion; and liver and kidneys were removed for determination of tissue glutathione (GSH) concentration, APAP concentration, and covalent binding. APAP at 1250 mg/kg induced nephrotoxicity (as indicated by elevations in BUN concentration) in 3-month-old females but not males, whereas APAP induced hepatotoxicity (as indicated by elevations in serum ALT activity) in 3-month-old males but not females. Sex differences in APAP toxicity were no longer apparent in 18-month-old rats. APAP at 750 mg/kg ip produced liver and kidney damage in 18-month-old but not 3-month-old male and female rats. No consistent sex- or age-dependent differences in serum, hepatic, and renal APAP concentrations were observed that would account for differences in APAP toxicity. No sex- or age-dependent differences in tissue GSH depletion or covalent binding of radiolabel from APAP in livers or kidneys were observed following APAP administration. Utilizing an affinity-purified polyclonal antibody raised against APAP, arylated proteins with electrophoretic mobility similar to those observed in mice were prominent in rat livers following APAP administration to 3- and 18-month-old rats of both sexes. In contrast, no arylated proteins were detected in any rat kidneys following APAP administration. Absence of immunochemically detectable proteins in rat kidney following APAP administration is in direct contrast to observations in mice and supports the hypothesis that mechanisms of APAP hepatotoxicity and nephrotoxicity in rats and mice are distinctly different. In conclusion, sex differences in APAP toxicity are observed only in young adult (3-month-old) rats and sex differences are organ-specific with males more susceptible to hepatotoxicity and females more susceptible to nephrotoxicity. Aging rats are more susceptible to APAP-induced damage to both the liver and the kidney than are 3-month-old rats but sex differences are no longer apparent in 18-month-old rats. The mechanisms contributing to sex- and age-dependent differences in APAP toxicity cannot be attributed to differences in tissue APAP concentrations, GSH depletion, or covalent binding.
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PMID:Sex- and age-dependent acetaminophen hepato- and nephrotoxicity in Sprague-Dawley rats: role of tissue accumulation, nonprotein sulfhydryl depletion, and covalent binding. 881 6


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