Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene (DCB) have been investigated. The objectives were to estimate the onset of toxicity and to further elucidate the role of cytochrome P450 in the metabolism and toxicity of these compounds. In a study design employing one animal per dose level, Fischer-344 rats were gavaged with up to 25 different dosages, then evaluated 24 h later. Hepatic necrosis, serum alanine aminotransferase, and serum aspartate aminotransferase exhibited similar patterns demonstrating that ortho-DCB (o-DCB) was the most toxic in terms of both earliest onset and degree of response at higher dosages. For these three endpoints, meta-DCB (m-DCB) exhibited a lesser toxicity. Para-DCB (p-DCB) did not cause changes in these three endpoints, but hepatic degenerative changes were found. Total hepatic cytochrome P450 responses were also different after treatment with each isomer. The o-DCB produced a dose-dependent decrease in P450 beginning at dosages lower than the onset of necrosis and appeared to be a suicide substrate for P450. The m-DCB treatment increased P450 at dosages below the onset of necrosis and decreased P450 at higher dosages, with the decline preceding the onset of hepatocyte death. Treatment with p-DCB increased P450 beginning at 380 mg/kg. The combination of toxicity and P450 profiles has provided a framework for interpreting literature data on the metabolism and toxicity of the DCBs in rats. It is also noteworthy that o-DCB and p-DCB were administered at dosages several times the oral rat LD-50 (RTECS) without any lethality.
 ...
PMID:The differential hepatotoxicity and cytochrome P450 responses of Fischer-344 rats to the three isomers of dichlorobenzene. 129 13

We report the development of severe hepatotoxicity in a patient on zidovudine therapy who received 3.3 g of acetaminophen in less than 36 hours. Three days later, the patient's serum aspartate aminotransferase level was 5,724 U/L, alanine aminotransferase was 3,124 U/L, lactate dehydrogenase was 12,675 U/L, alkaline phosphatase was 84 U/L, and total bilirubin was 20 mumol/L. These values substantially improved over the ensuing 4 days. Serologic results for hepatitis B, hepatitis A, and cytomegalovirus were all negative. The pattern and time sequence of transaminase elevation in this patient are consistent with acute acetaminophen hepatotoxicity, especially since zidovudine-induced hepatotoxicity is described as producing cholestasis rather than acute hepatitis. We hypothesize that our patient's susceptibility to acetaminophen-dependent hepatotoxicity may have been augmented by competitive utilization of glucuronidation by other drugs such as zidovudine and/or trimethoprim-sulfamethoxazole with subsequent increased cytochrome P450-dependent metabolism of acetaminophen. Additionally, due to malnutrition and/or to human immunodeficiency virus infection per se, our patient may have had decreased hepatic reserves of glutathione with which to conjugate the toxic acetaminophen product of the P450 system. Although severe acetaminophen-associated hepatotoxicity has not previously been reported in patients receiving zidovudine, we suggest that clinicians be aware of this potential interaction and counsel malnourished patients, especially those with concomitant hepatic disease, to exercise caution when taking both these medications.
 ...
PMID:Severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine. 836 34

alpha-Naphthylisothiocyanate (ANIT) injures bile duct epithelium and hepatic parenchymal cells in rats. It is commonly believed that ANIT must undergo bioactivation by hepatic, cytochrome P450-dependent mixed-function oxidases (MFO), since agents which are inducers or inhibitors of hepatic MFO activity enhance or attenuate, respectively, the liver injury associated with ANIT. Several of these agents also affect hepatic glutathione (GSH) content and/or GSH S-transferase activity in a manner to suggest a causal role for GSH in ANIT-induced hepatotoxicity. To determine whether GSH might be involved in the mechanism of injury, buthionine sulfoximine (BSO), diethyl maleate (DEM), or phorone was used to reduce hepatic non-protein sulfhydryl (NPSH) content, an indicator of GSH content. Twenty-four hours after ANIT treatment, rats exhibited cholestasis and elevations in serum of total bilirubin concentration, total bile acid concentration, aspartate aminotransferase (AST) activity, and gamma-glutamyltransferase activity. Cotreatment of rats with BSO decreased NPSH content by 70% at 24 hr and prevented the cholestasis and elevations in serum markers of liver injury caused by ANIT. Likewise, cotreatment of rats with DEM afforded protection against markers of liver injury. Phorone treatment attenuated ANIT-induced elevations in serum total bilirubin concentration and AST activity. Although BSO treatment afforded protection against ANIT-induced liver injury at 24 hr, the injury was evident at 48 hr, and it appeared to coincide with a return of hepatic NPSH content. These results suggest that GSH plays a causal or permissive role in the liver injury caused by ANIT.
 ...
PMID:Protection against alpha-naphthylisothiocyanate-induced liver injury by decreased hepatic non-protein sulfhydryl content. 167 29

The immunotoxicity, hepatotoxicity, and nephrotoxicity of subacute exposure to carbon tetrachloride (CCl4) were evaluated in young adult (8-9 weeks old) male Fischer 344 rats dosed by gavage with CCl4 for 10 consecutive days at 0, 5, 10, 20 or 40 mg/kg/day. Two days following the last treatment rats were evaluated for alterations in immune function by monitoring the following: body and lymphoid organ weights; mitogen and mixed leukocyte reaction lymphoproliferative responses; natural killer cell activity; and cytotoxic T lymphocyte responses. A separate group of similarly dosed rats was immunized with sheep red blood cells (SRBC) on Day 9 of dosing, and the primary antibody response was assessed 4 days later. Hepatic and renal toxicity were assessed 2 days after the last treatment by monitoring organ weights, serum indicators of hepatic and renal damage, and hepatic cytochrome P450 levels, as well as by histological evaluation. Significant increases in relative liver weights were observed in rats dosed at 40 mg/kg/day. Histologically, these livers displayed mild to moderate vacuolar degeneration and minimal to mild hepatocellular necrosis. In addition, serum levels of aspartate aminotransferase and alanine aminotransferase were elevated at this dosage, as well as at 20 mg/kg/day. There were no renal effects observed at these dosages of CCl4. In addition, no consistent alterations were observed in the immune parameters examined in these same animals nor in the rats immunized with SRBC. Furthermore, there was no difference in the antibody response to SRBC in another set of rats dosed at 40, 80 or 160 mg/kg/day CCl4. These results indicate that CCl4 is not immunotoxic in the rat at dosages that produce overt hepatotoxicity.
 ...
PMID:Immunotoxicologic assessment of subacute exposure of rats to carbon tetrachloride with comparison to hepatotoxicity and nephrotoxicity. 183 55

The present investigation was undertaken to test our hypothesis that the slow responses of hepatocellular regeneration and tissue repair after CCl4-induced liver injury are responsible for the high sensitivity of gerbils to the hepatotoxic and lethal effects of CCl4. These studies were conducted in normal and actively regenerating livers using male gerbils 5 or 15 days after partial (2/3) hepatectomy (PH5 and PH15, respectively), or those undergoing sham operation (SH). An LD50 dose of CCl4 (80 microL/kg, i.p.) resulted in a mortality (21%) significantly (P less than 0.05) less than 50% in PH5 gerbils 48 hr after CCl4 administration, whereas the mortality observed in PH15 or SH gerbils was not significantly different from 50%. The elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly (P less than 0.05) less in PH5 gerbils than in PH15 or SH groups after the administration of either the LD50 dose or a low dose (15 microL/kg) of CCl4. Histopathological and histomorphometric examinations also indicated that CCl4-induced liver injury was less severe in PH5 gerbils than in the PH15 and SH groups. The hepatic microsomal cytochrome P450 content measured before CCl4 administration in the PH5 gerbils was decreased (26%) significantly (P less than 0.05) as compared with the SH group, but was not significantly different from that of PH15 gerbils. In vivo metabolism of 14CCl4 and lipid peroxidation in liver tissue were not significantly different among the various groups. Therefore, the protection against CCl4 toxicity observed in PH5 gerbils is unlikely to be due to decreased bioactivation of CCl4 or lipid peroxidation in that group. [3H]Thymidine incorporation into hepatocellular nuclear DNA was 4- to 5-fold higher in PH5 gerbils than in the PH15 and SH groups, indicating active hepatocellular proliferation in PH5 gerbils. [3H]Thymidine incorporation was further increased significantly (P less than 0.05) 24 hr after challenge with a low dose of CCl4 in PH5 gerbils, whereas it remained low until 48 hr after the CCl4 injection in the PH15 or SH group. The protection against CCl4 toxicity afforded by partial hepatectomy was closely associated with active hepatocellular regeneration. The overall results confirm the concept that the high sensitivity of gerbils to CCl4 is due to very sluggish hepatocellular regeneration and tissue repair response to the CCl4-induced liver injury.
 ...
PMID:Protection from CCl4 toxicity by prestimulation of hepatocellular regeneration in partially hepatectomized gerbils. 185 67

The destruction of liver microsomal cytochromes P450 by a previously administered low dose of CCl4 has been widely accepted as the mechanism of CCl4 autoprotection. However, circumstantial evidence suggests that this mechanism cannot completely explain the phenomenon of autoprotection. The protective effect of a low dose of CCl4 (0.3 ml/kg, po) on the lethal effect of a subsequently administered high dose (5 ml/kg, po) was established in male Sprague Dawley rats. The protective dose permitted 100% survival, whereas only 15% survival was observed without it. Hepatotoxicity, measured by serum enzyme elevations (aspartate transaminase, alanine transaminase, and sorbitol dehydrogenase) and histopathological changes 24 hr after the treatment with high dose, was similar in both the groups, even though the protective dose had significantly decreased liver microsomal cytochromes P450 (to 62% of normal) and associated enzymes, aminopyrine demethylase and aniline hydroxylase. Rats pretreated with CoCl2 to decrease hepatic microsomal cytochrome P450 to 44% of normal levels did not show a significant protection from the hepatotoxicity of high dose of CCl4. Previous studies have established that hepatocellular regeneration is stimulated within 6 hr after the administration of a low dose of CCl4. Based on this observation, a premise that autoprotection results from augmented recovery from injury rather than decreased injury appears likely. Hence, the role of hepatocellular regeneration was evaluated by following 3H-thymidine incorporation in hepatocellular nuclear DNA, labelling index by autoradiography, and by morphometric estimation of mitotic index. After administration of the protective dose of CCl4, stimulated nuclear DNA synthesis measured by 3H-thymidine incorporation into nuclear DNA was increased and this remained high even after subsequent administration of high dose of CCl4. Forty-eight hr after the administration of a lethal dose of CCl4 alone (5 ml/kg, po), labelling index was slightly increased, but mitotic index was not increased. In the surviving rats (15%), both labelling index and mitotic index were significantly elevated after an additional 24 hr. In rats receiving the protective dose, a significantly greater elevation of labelling index as well as mitotic index occurred 48 hr after the administration of the same lethal dose of CCl4. These results suggest that hepatocellular regeneration stimulated by the protective dose, as a biological response recruited to overcome the accompanying limited injury, may augment and sustain tissue repair processes to permit tissue restoration even after the massive liver injury elicited by the subsequent large dose of CC14.
 ...
PMID:Role of hepatocellular regeneration in CCl4 autoprotection. 204 7

Two decades of research in ethanol metabolism have culminated in the molecular elucidation of an ethanol-inducible cytochrome P450 (P450IIE1) which is not only involved with ethanol metabolism and ethanol tolerance, but also with the activation of a number of xenobiotics. The unique ability of P450IIE1 to activate xenobiotic agents now appears to be responsible for the increased susceptibility of the heavy drinker to hepatotoxic industrial solvents, commonly used drugs, over-the-counter medications and chemical carcinogens. It also explains some of the interaction of ethanol with nutritional factors, such as hepatic vitamin A: enhanced microsomal degradation of retinoids (together with hepatic mobilisation) promotes depletion. Treatment, however, is complicated by the fact that ethanol also enhances the toxicity of excess vitamin A. All pathways of ethanol metabolism result in the production of acetaldehyde, the toxicity of which has been reviewed (Lieber 1982). New aspects discussed here include the formation of acetaldehyde-protein adducts and an associated immune response that may play a pathogenic role. Also discussed are the implications of ethanol-induced alterations in microtubules, mitochondria and plasma membranes, as they relate, in part, to accompanying acetaldehyde-induced toxicity, to the production of free radicals or to lipid peroxidation-mediated injury associated with glutathione depletion. There is also depletion of S-adenosyl-L-methionine (SAMe). Administration of synthetic SAMe results in a partial correction of the SAMe depletion and a consequent restoration of glutathione levels. Other beneficial effects of SAMe include a significant attenuation of the increase in plasma aspartate transaminase and glutamate dehydrogenase activities. Mitochondrial damage, including giant forms, documented by light and electron microscopy, is also attenuated by SAMe. Thus, the new understanding of the pathophysiology of alcohol-induced liver damage has led to more successful therapy with drugs and nutritional factors.
 ...
PMID:Interaction of alcohol with other drugs and nutrients. Implication for the therapy of alcoholic liver disease. 208 78

The effect of praziquantel in different concentrations on isolated rat hepatocytes as a cellular target was studied to detect any possible toxicity. Leakage of cytosolic enzymes, aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase (LDH) was monitored after one hour of incubation of all the cells with the drug. Levels of reduced glutathione (GSH) and cytochrome P450 were also assayed. The drug, in concentrations of 5, 25, 50 and 100 micrograms/ml, had no effect on any of these parameters. In contrast, the hepatotoxic compound trichloroethylene showed dose-dependent toxicity, as measured by trypan blue (TB) exclusion, LDH leakage, and reduction in GSH content in the present cellular model. These results suggest that praziquantel is a relatively safe drug with respect to liver function.
 ...
PMID:Praziquantel did not exhibit hepatotoxicity in a study with isolated hepatocytes. 214 53

To determine the course of hepatic recovery from subchronic oral administration of carbon tetrachloride (CCl4), male F-344 rats were gavaged with 0, 20, or 40 mg CCl4/kg, 5 days/week, for 12 weeks. Exposure to CCl4 caused dosage-dependent increases in relative liver weight and the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, and cholesterol as well as a dosage-dependent decrease in hepatic cytochrome P450. Centrilobular hepatocellular vacuolar degeneration, necrosis, and cirrhosis occurred at both 20 and 40 mg/kg, with dosage-dependent severity. Reversibility of these reported effects varied with parameter. By Day 8 postexposure, necrosis had disappeared and all serum indicators and cytochrome P450 had returned to control levels. By Day 15 postexposure, the severity of the vacuolar degeneration had decreased. Reversibility of cirrhosis was dosage dependent; complete recovery occurred in the low- but not the high-dose group by Day 15. The disappearance of the increase in relative liver weight was also dependent on dosage; the low- but not the high-dose group had returned to the control level by Day 22. In an attempt to measure persistent hepatic damage, liver uptake relative to the spleen was determined for a sulfur colloid labeled with technetium-99m and for tritiated 2-deoxyglucose. Neither method consistently measured hepatic damage in cirrhotic livers due, in part, to the high degree of variability in the tracer uptake data.
 ...
PMID:Assessment of hepatic indicators of subchronic carbon tetrachloride injury and recovery in rats. 225 19

Coleonol, a diterpine prevented biochemical changes induced by coronary artery ligation in rabbits at a dose of 10 mg/kg, iv. It increased the heart mitochondrial oxygen uptake and O ratio, which may be responsible for the stabilization of heart membrane. The decrease in serum creatine phosphokinase, glutamate oxaloacetate transaminase, glutamate pyruvate transaminase phospholipase and lipid peroxide and increase in cytochrome P450, glycogen and superoxide dismutase activity by coleonol treatment could have contributed to restore myocardial integrity and cardiac function disturbed by coronary artery ligation. The cardioprotective activity of coleonol was found to be comparable to propranolol.
 ...
PMID:Protective effect of coleonol on biochemical changes produced in coronary ligation induced ischemia. 227 71


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