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 protective activity of 1,2-bis(3,5-dioxopiperazin-l-yl)propane (ICRF-187) and dimethyl sulfoxide (DMSO) was tested against acetaminophen-induced hepatotoxicity. Male Syrian golden hamsters injected intraperitoneally between 18:00 h and 20:00 h for 2 consecutive days with acetaminophen (N-acetyl-p-aminophenol) (300 mg/kg) displayed signs of hepatotoxicity as evidenced by increases in enzyme activity and cellular damage. Forty-eight hours after the second acetaminophen dose, the activities of serum glutamic-pyruvic transaminase and alkaline phosphatase were increased compared with levels found in hamsters given only saline. In addition, hepatocellular necrosis was evident in acetaminophen-treated animals. ICRF-187 (300 mg/kg) given 1 h before acetaminophen attenuated the increases in enzyme activities, and both DMSO (7.3 g/kg) and ICRF-187 reduced the incidence and severity of acetaminophen-induced hepatocellular injury. Both ICRF-187 and DMSO are capable of altering free radical-mediated toxicity in other experimental systems. Whether these compounds reduce acetaminophen-induced liver toxicity by a similar mechanism remains to be determined.
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PMID:Examination of the protective effect of ICRF-187 and dimethyl sulfoxide against acetaminophen-induced hepatotoxicity in Syrian golden hamsters. 641 37

Halogenated anilines and aminophenols are nephrotoxicants and hepatotoxicants in mammals. The purpose of this study was to determine the in vivo and in vitro nephrotoxic and hepatotoxic potential of 4-amino-2,6-dichlorophenol, a putative metabolite of 3,5-dichloroaniline. In the in vivo experiments, male Fischer 344 rats (four/group) were administered a single intraperitoneal (i.p.) injection of 4-amino-2,6-dichlorophenol (0.25, 0.38 or 0.50 mmol/kg) or vehicle (dimethylsulfoxide (DMSO), 1.0 ml/kg) and renal and hepatic function monitored for 48 h. Only minor changes in function or morphology were observed in the 0.25 mmol/kg treatment group. However, in the 0.38 mmol/kg treatment group evidence of both nephrotoxicity and hepatotoxicity were evident. Nephrotoxicity was characterized by increased proteinuria, glucosuria, hematuria, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased p-aminohippurate (PAH) accumulation and proximal tubular necrosis in the corticomedullary region of the kidney. Hepatotoxicity was characterized by elevated plasma alanine aminotransferase (ALT/GPT) activity and liver weight. Animals administered the 0.5 mmol/kg dose died within 24 h. In the in vitro experiments, the effect of 4-amino-2,6-dichlorophenol on organic ion accumulation, gluconeogenesis and lactate dehydrogenase (LDH) leakage was quantitated in liver and/or renal cortical slices. Organic anion accumulation was inhibited in renal cortical slices by 4-amino-2,6-dichlorophenol bath concentrations of 5 x 10(-6) M or higher, while organic cation uptake was decreased at 4-amino-2,6-dichlorophenol bath concentrations of 1 x 10(-5) M or greater. Renal and hepatic pyruvate-stimulated gluconeogenesis were inhibited and renal LDH leakage increased at 4-amino-2,6-dichlorophenol bath concentrations of 5 x 10(-5) M or greater. Increased LDH leakage from liver slices was not observed. These results demonstrate that 4-amino-2,6-dichlorophenol is a nephrotoxicant and hepatotoxicant in vivo and in vitro and that the kidney is more susceptible to 4-amino-2,6-dichlorophenol toxicity than the liver.
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PMID:In vivo and in vitro 4-amino-2,6-dichlorophenol nephrotoxicity and hepatotoxicity in the Fischer 344 rat. 802 37

The role of leukotriene (LT) on liver regeneration after hepatectomy is still unknown. LTB4 stagnates in the liver with obstructive jaundice, because LTB4 is excreted in the bile; therefore, LTB4 may have an effect on liver regeneration after hepatectomy with obstructive jaundice. Release of obstructive jaundice and simultaneous 70% hepatectomy was performed in rats to study the effect of 5-lipoxygenase inhibitor (AA-861) on liver regeneration. Group 1 underwent hepatectomy with administration of 0.1 mL dimethyl sulfoxide (DMSO), group 2 underwent hepatectomy with administration of AA-861 (20 mg/kg/d) dissolved in 0.1 mL DMSO, group 3 underwent hepatectomy with administration of AA-861 (40 mg/kg/d) dissolved in 0.1 mL DMSO, group 4 underwent release of obstructive jaundice and hepatectomy with administration of 0.1 mL DMSO, and group 5 underwent relief of obstructive jaundice and hepatectomy with administration of AA-861 (20 mg/kg/d). DMSO or AA-861 was administered 24 hours before, during, and 24 hours after hepatectomy in each group. Whole blood LTB4 and serum alanine aminotransferase (ALT), total bilirubin, and bromodeoxyuridine labeling index (LI) were measured before and after hepatectomy. The LTB4 level increased during obstructive jaundice and after hepatectomy. LTB4 and serum ALT levels were significantly lower after hepatectomy in the rats that were administered AA-861, and a significantly higher LI was observed at 24 hours after hepatectomy in rats receiving AA-861. Inhibition of 5-lipoxygenase promotes liver regeneration and decreases hepatocyte injury after hepatectomy associated with obstructive jaundice.
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PMID:Inhibition of 5-lipoxygenase promotes the regeneration of the liver after partial hepatectomy in normal and icteric rats. 861 35

Dimethyl sulfoxide (DMSO) can protect the liver from injury produced by a variety of hepatotoxicants when administered prior to or concomitant with the toxicants. This protective action has previously been attributed to DMSO-induced inhibition of bioactivation of the compounds to toxic intermediates. In these studies, the ability of DMSO to provide protection when administered 10 hr after a toxicant was evaluated in several animal models of xenobiotic-induced liver and kidney injury. In the guinea pig model of halothane-associated hepatotoxicity, male outbred Hartley guinea pigs received 2 ml/kg DMSO 10 hr after an inhalation exposure to 1.0% halothane, 40% O2 for 4 hr. DMSO decreased the extent of liver necrosis as indicated by a threefold decrease in plasma alanine aminotransferase activity 48 hr after exposure and a reduction in the incidence and extent of zone 3 necrosis. These results do not appear to be due to alterations in halothane biotransformation since DMSO administered at 10 hr after halothane had no affect on plasma concentrations of the halothane metabolite tritluoroacetic acid or covalent binding by reactive halothane biotransformation intermediates to hepatic protein. In addition, administration of the structurally analogous biotransformation inhibitor diallyl sulfide at 10 hr after halothane also had no affect on biotransformation or covalent binding but provided no protection from liver injury. Hepatic glutathione concentrations in the guinea pigs 24 hr after halothane exposure were also unaffected by late treatment with DMSO. Further studies in male Sprague-Dawley rats demonstrated the ability of DMSO to decrease the hepatic injury resulting from oral administration of 1.0 ml/kg chloroform or 0.5 ml/kg bromobenzene when administered 10 hr after either toxicant. The chloroform-treated rats also developed renal tubular necrosis with large increases in plasma creatinine and urea nitrogen, which were completely ameliorated by DMSO. Elucidating the mechanism(s) of this protective action of late DMSO administration should provide insight into the cascade of events that lead to liver and kidney injury from toxicants and, hopefully, therapeutic modalities for individuals suffering from acute, progressing, xenobiotic-induced hepatitis.
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PMID:Late dimethyl sulfoxide administration provides a protective action against chemically induced injury in both the liver and the kidney. 900 50

The nuclear enzyme poly(ADP-ribose) synthetase (PARS) is activated by DNA strand breakage, caused, for example by nitric oxide (NO), peroxynitrite, or oxygen-derived free radicals. Activation of PARS can cause intracellular energy depletion and cell death in vitro and may play a role in the circulatory and organ failure caused by endotoxin (LPS). Here we investigate the effects of various chemically distinct inhibitors of PARS activity (3-aminobenzamide, nicotinamide, 1,5-dihydroxyisoquinoline) on circulatory failure and organ dysfunction caused by LPS in the rat. Administration of endotoxin caused circulatory failure, acute renal dysfunction, hepatocellular injury and dysfunction, pancreatic injury, elevation of plasma lactate levels, and overproduction of NO. None of the PARS inhibitors used reduced the circulatory failure, the renal dysfunction, rise in lactate, or the overproduction of NO caused by LPS. Although 1,5-dihydroxyisoquinoline (ISO) attenuated the rises in the serum levels of bilirubin, alanine aminotransferase (ALT) (indicators of liver injury/dysfunction), and lipase (indicator of pancreatic injury); a similar effect was also observed with the vehicle for ISO, dimethyl sulfoxide (DMSO), which is a well known scavenger of hydroxyl radicals. Thus, the beneficial effects of ISO are unlikely to be due to inhibition of PARS activity, but may be due to the scavenging of free radicals by its vehicle DMSO. Activation of PARS does not contribute to the circulatory failure, renal dysfunction, lactic acidosis, or the overproduction of NO and is unlikely to contribute to the liver injury/dysfunction caused by endotoxic shock in the rat.
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PMID:Effects of inhibitors of poly(ADP-ribose) synthetase activity on hypotension and multiple organ dysfunction caused by endotoxin. 968 85

Dimethyl sulfoxide (DMSO) has previously been reported to protect against hepatotoxicity resulting from chloroform (CHCl3) or bromobenzene (BB) when given 10 hr after the toxicant. The object of these studies was to further demonstrate the latent protective ability of DMSO by administering it at a much later time (24 hr) following toxicant exposure. In addition, a more detailed evaluation of the lesions was performed to better characterize the lesion progression and resolution. Male Sprague-Dawley rats received a hepatotoxic oral dose of either CHCl3 (1.0 ml/kg) or BB (0.5 ml/kg) and then received 2 ml/kg DMSO intraperitoneally 24 hr later. With both toxicants, limited centrilobular lesions were already present by the time DMSO was administered. Without treatment, liver injury rapidly progressed so that by 48 hr it occupied 40-50% of the liver, with accompanying large increases in plasma alanine aminotransferase (ALT) activity. Administration of DMSO greatly attenuated lesion development for both toxicants; the area injured was reduced by more than 4-fold, accompanied by a decrease in 48 hr ALT activity of 8-16-fold. The ability of DMSO to intervene in the development of liver injury at such a late time appears to be unique and may provide insight into therapies for acute xenobiotic-induced hepatitis.
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PMID:Hepatoprotection by dimethyl sulfoxide. I. Protection when given twenty-four hours after chloroform or bromobenzene. 1035 11

The effects of cycloprodigiosin hydrochloride (cPrG-HCl), a new H(+)/Cl(-) symporter, were examined in liver cancer cell lines in vitro and in vivo. In the in vitro MTT assay, cPrG-HCl inhibited the growth of 6 liver cancer cell lines (Huh-7, HCC-M, HCC-T, dRLh-84, and H-35, hepatocellular carcinoma; HepG2, hepatoblastoma) in a dose- and time-dependent manner. The 50% inhibitory concentrations (IC(50)) at 72 hours' treatment for liver cancer cell lines were 276 to 592 nmol/L, while that for isolated normal rat hepatocyte was 8.4 micromol/L. The cPrG-HCl treatment of Huh-7 cells induced apoptosis as confirmed by the appearance of a subG(1) population, intranucleosomal DNA fragmentation, and chromatin condensation. cPrG-HCl raised the pH of acidic organelles and lowered pHi (below pH 6.8). In addition, the apoptosis in Huh-7 cells induced by cPrG-HCl was strongly suppressed when the cells were cultured with imidazole, a cell-permeable base. In the in vivo assay, nude mice bearing subcutaneous xenografted Huh-7 cells received 2 weeks of treatment with cPrG-HCl (1 or 10 mg/kg/d) subcutaneously. This treatment significantly inhibited tumor growth compared with the control after 8 days. The control mice were treated with 1% dimethylsulfoxide (DMSO) in saline (vehicle). A histopathological examination using the terminal deoxynucleotidyl transferase mediated dUTP biotin nick end labeling (TUNEL) method showed apoptosis in the treated tumor cells. No pathological changes were observed in any organs, and the serum alanine transaminase levels remained within normal limits. These results suggest that cPrG-HCl may be useful for the treatment of hepatocellular carcinoma.
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PMID:Cycloprodigiosin hydrochloride, a new H(+)/Cl(-) symporter, induces apoptosis in human and rat hepatocellular cancer cell lines in vitro and inhibits the growth of hepatocellular carcinoma xenografts in nude mice. 1049 40

1 Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by strand breaks in DNA, which are caused by reactive oxygen species (ROS). Here we investigate the effects of the PARS inhibitors 3-aminobenzamide (3-AB), nicotinamide and 1,5-dihydroxyisoquinoline (ISO) on the circulatory failure and the organ injury/dysfunction caused by haemorrhage and resuscitation in the anaesthetized rat. 2 Haemorrhage (sufficient to lower mean arterial blood pressure to 50 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure to 66+/-4 mmHg (control, n=13). This circulatory failure was not affected by administration (5 min prior to resuscitation) of 3-AB (10 mg kg-1 i.v., n=7), nicotinamide (10 mg kg-1 i.v., n=6) or ISO (3 mg kg-1 i.v., n=6). 3 Haemorrhage and resuscitation also resulted in rises in the serum levels of urea and creatinine. This renal dysfunction was attenuated by 3-AB and nicotinamide, but not by nicotinic acid (n=7), an inactive analogue of nicotinamide. Although ISO (n=6) also attenuated the renal dysfunction caused by haemorrhage and resuscitation, its vehicle (10% DMSO, n=4) had the same effect. 4 Haemorrhagic shock resulted in enhanced serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lipase, indicating the development of hepatocellular and pancreatic injury, respectively. Similarly, haemorrhagic shock also resulted in an increase in the serum levels of creatine kinase (CK) indicating the development of neuromuscular injury. This was attenuated by 3-AB and nicotinamide, but not by nicotinic acid. Although ISO also attenuated the liver, pancreatic and neuromuscular injury caused by haemorrhagic shock, its vehicle had the same effect. 5 Thus, activation of PARS contributes to the organ injury and dysfunction caused by haemorrhage and resuscitation in the rat.
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PMID:Effects of inhibitors of the activity of poly (ADP-ribose) synthetase on the organ injury and dysfunction caused by haemorrhagic shock. 1057 50

Phenolic antioxidants, such as butylated hydroxyanisole (BHA) and propyl gallate (PG), have demonstrated paradoxical cancer initiating and preventive actions in animals. Studies examining the disposition and biological effects of these agents have used solutions in ethanol-saline, PEG400-saline, corn oil, or DMSO. The aim of this study was to compare the pharmacokinetics of BHA and PG in mice following dosing in either a "control" dosing vehicle (ethanol-saline, 2:3) or a solution of an inclusion complex of each agent with hydroxypropyl-beta-cyclodextrin (HPB) in saline. Results demonstrate that BHA or PG are rapidly absorbed and eliminated in mice following i.p. or p.o. dosing in either dosing vehicle. Pharmacokinetic parameters of BHA estimated in mice correlated with those reported for other species, including humans ("Interspecies Scaling"), suggesting that exposures are proportional to body weight across species. Therefore, rodents are appropriate animal models to study these phenolic antioxidants. The oral absorption of PG was influenced by dosing vehicle in mice, suggesting the need for cautious selection of traditional nonaqueous vehicles (such as DMSO, ethanol, etc.) in the investigation of biological activities of these xenobiotics. Indeed, DMSO elevated plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) concentrations following subchronic i.p. administration of various blank vehicles to mice. Such elevations in plasma concentrations of these enzymes are considered biomarkers of hepatotoxicity. The absolute oral bioavailability of PG (administered as an HPB complex) in rats was low (5%) suggesting extensive metabolism or incomplete absorption. The low oral bioavailability of these phenolic antioxidants in rodents suggests that the risk assessment of these antioxidants should include an evaluation of their metabolites as well.
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PMID:Influence of dosing vehicles on the preclinical pharmacokinetics of phenolic antioxidants. 1060 82

Dimethyl sulfoxide (DMSO) has previously been shown to attenuate chloroform (CHCl3) and bromobenzene (BB) induced hepatotoxicity in the rat when a dose of 2.0 ml/kg is given 24 hr after the toxicants. However, the optimal dose of DMSO and the latest time at which DMSO can be administered and still provide effective protection have not been determined. In order to determine the latest time at which DMSO can interrupt the development of necrosis, male Sprague Dawley rats received either 0.75 ml/kg CHCl3 or 0.5 ml/kg BB, 20% in corn oil, p.o., followed by single dose of 2 ml/kg DMSO, 50% in saline, i.p., at 24, 26, 28 or 30 hr later. Positive control groups received either CHCl3 or BB and then 4.0 ml/kg saline, i.p., 24 hr later. All of the animals were then killed 48 hr after toxicant dosing. The extent of liver injury present when DMSO was administered was examined by killing animals at 24, 26, 28 or 30 hr after toxicant dosing. The optimal dose of DMSO for providing protection was estimated by administering either 0, 1.0, 2.0, 3.0 or 4.0 ml/kg DMSO at 24 hr after toxicant dosing and then killing the animals at 48 hr. Delaying DMSO administration to times later than 24 hr after toxicant dosing led to a loss of protection as indicated by both plasma ALT activity and the light microscopic appearance of liver tissue. The distinctive liver lesions present at 24 hr after CHCl3 or BB dosing rapidly expanded from being limited around central veins to bridging between centrilobular areas in only a few hours. This was accompanied by large increases in plasma ALT. With both toxicants, doses of DMSO greater than 2 ml/kg did not enhance its protective action while the lower dose of 1 ml/kg DMSO was not as effective. The loss of DMSO's antidotal action when given at times later than 24 hr after the toxicants indicates irreversible changes were underway as the centrilobular lesions progressed from being limited to more bridging in nature. Hopefully, further elucidation of the mechanism(s) by which DMSO interrupts the rapid progression of injury will both help to understand the steps involved in lesion development and provide insights into therapeutic interventions for drug and chemical induced hepatitis.
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PMID:Hepatoprotection by dimethyl sulfoxide. II. Characterization of optimal dose and the latest time of administration for effective protection against chloroform and bromobenzene induced injury. 1066 12


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