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:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A possible role of metabolic activation by cytochrome P450 (P450) in thioacetamide-induced hepatotoxicity was investigated in male BALB/c mice. The mice were pretreated with the P450 inducer, beta-ionone, subcutaneously at 600 mg/kg, 72 and 48 h prior to an intraperitoneal administration of either 100 or 200 mg/kg of thioacetamide. The elevated activities of serum alanine aminotransferase and serum aspartate aminotransferase by thioacetamide were greatly potentiated by the pretreatment with beta-ionone. Moreover, the potentiation of thioacetamide-induced hepatotoxicity was also observed in the histopathological examination of livers. The hepatic necrosis by thioacetamide was potentiated when mice were pretreated with beta-ionone. In liver microsomes, the activities of P450 2B-specific pentoxyresorufin O-depentylase and benzyloxyresorufin O-debenzylase were significantly induced by the treatment with beta-ionone. Beta-ionone also induced other P450-associated monooxygenases. Because the pretreatment with beta-ionone was not hepatotoxic at the dose inducing P450s. our present results suggest that beta-ionone may be a useful model inducer of P450 enzyme(s) in studying toxic mechanism of certain chemicals which require metabolic activation by P450s in mice.
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PMID:Pretreatment of male BALB/c mice with beta-ionone potentiates thioacetamide-induced hepatotoxicity. 1009 55

There are few reports regarding the effects of benzene and ethanol being administered simultaneously. In our experiments with 4 groups (controls, ethanol, benzene and ethanol plus benzene) Wistar male rats were treated with ethanol (20%) for 5 weeks, and then exposed to benzene (0.26 g/kg) for 5 days per week for 3 weeks. We also investigated the effects of benzene on the body weight, organ weight, peripheral hematology and hepatic drug metabolizing enzymes in the ethanol administrated rats. The liver weight increased significantly, but spleen weight decreased significantly in the benzene exposed group. Hematological examination showed a decrease of leukocyte in the two groups of benzene and ethanol plus benzene in comparison with the controls, but an effect promoted by ethanol was not found. Serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) values were not significantly different in the exposure groups when compared with the controls. The contents of microsomal cytochrome P450 in all the exposed groups showed a tendency to increase, but they were not significantly different in comparison with the controls. On the other hand, hepatic glutathione S-transferase activity in the exposed groups increased significantly.
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PMID:[Effect of benzene exposure on hematology and hepatic drug metabolic enzymes in ethanol administrated rats]. 1020 90

In this experiment, we studied the different changes in activities and protein levels of each subform of hepatic cytochrome P450 and glutathione S-transferase (GST), in chemical-induced liver injury in rats. Rats were administered 1,1-dichloroethylene (DCE), allyl alcohol (AA), bromobenzene (BB) and N,N-dimethylformamide (DMF) p.o. once every two days for 7 times, and decapitated 18 hr after the last administration. DCE and AA showed stronger hepatic toxicity than BB and DMF, as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were higher in DCE and AA treated rats than in BB and DMF groups. Anti-cytochrome P450 inhibitable activity of toluene metabolism and/or immunoblot analysis showed that CYP2E1 and CYP2B1/2 were induced by BB and DMF, but not by the other two chemicals; CYP2C11 was greatly decreased by all of the four toxicants; and CYP1A1/2 was slightly reduced by the four treatments. These changes were reflected in testosterone metabolism. Formation of 6 beta- and 7 alpha-hydroxytestosterone from testosterone was enhanced only in DMF-treated rats, whereas that of 2 alpha- and 16 alpha-hydroxytestosterone was reduced by all of the four chemicals. Serum GST activity was increased only in BB and DMF treated rats, but liver cytosolic GST activity was enhanced by all of the four hepatotoxicants, with higher values in BB and DMF groups than in DCE and AA groups. Immunoblot analysis demonstrated that GST Yp was induced by BB and DMF treatments, and Ya and Yc were increased only by BB. GST Yk and Yb1 were not affected by the treatments. The different change patterns of enzymes by a specific toxin and the similar modifying effect on a specific enzyme by different toxins were discussed in relation to the liver damage and to the heterogeneous distribution of enzymes in liver.
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PMID:Different change patterns of the isozymes of cytochrome P450 and glutathione S-transferases in chemically induced liver damage in rat. 1054 60

Dietary habits are often considered as a pathogenic factor for fatty liver. The impact of dietary intake and steatosis on drug metabolism remains poorly investigated. Our aim was to assess the effect of dietary intake on in vivo cytochrome P450 (CYP) activities in eleven patients with abnormal liver function tests potentially due to fatty liver and associated with a high-sugar diet. Liver function tests, liver volume, aminopyrine breath test (ABT) and chlorzoxazone (CZ) pharmacokinetics (area under the curve, AUC) which are known to reflect CYP2E1 activity were evaluated before and after 2 months restriction of dietary sugar intake. Features at inclusion were an increased BMI (30.3 (SD 3.2) kg/m2), high hepatic volume (1.96 (SD 0.48) litres), hyperechogenic liver parenchyma, elevated liver enzyme activities (alanine aminotransferase (EC 2.6.1.2) 58.6 (SD 17.4) IU/1 with alanine aminotransferase: aspartate aminotransferase (EC 2.6.1.1) ratio > 1), together with a normal ABT value (0.68 (SD 0.21)% specific activity of administered dose of [14C]aminopyrine in breath after 1 h) and a high CYP2E1 activity (CZ AUC 20.3 (SD 7.1) micrograms/ml per h). A dietary sugar restriction was prescribed. On the basis of repeated interviews by the same dietitian, unaware of any clinical and biochemical data, six patients remained complaint to the diet and exhibited reductions in BMI (P < 0.001), serum alanine aminotransferase (P = 0.008), liver volume (P = 0.002) and CYP2E1 activity (P = 0.007), a significant increase in ABT (P < 0.001) together with the disappearance of liver hyperechogenicity at ultrasound. In contrast, the five non-compliant patients did not show any significant change in any of these variables. In conclusion, CYP2E1 activity is induced in patients with perturbations of liver function tests potentially due to fatty liver. In these patients, effective dietary sugar restriction is associated with a reduction in liver volume, a reduction in CYP2E1 activity and an increased aminopyrine metabolism rate.
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PMID:Dietary restriction of energy and sugar results in a reduction in human cytochrome P450 2E1 activity. 1065 74

The ability of phenobarbital to induce the expression and activity of microsomal drug monooxygenases in the liver presents one of the most important issues in the field of chemical interactions and in the toxicity of xenobiotics. The model of rat liver injury induced by a single dose of thioacetamide (500 mg/kg intraperitoneally) was used to study the effect of phenobarbital (80 mg/kg/day intraperitoneally) for 5 days prior to thioacetamide. Serum parameters of liver injury such as aspartate aminotransferase activity, gamma-glutamyl transferase activity and the total bilirubin levels, as well as the activities of hepatic FAD and cytochrome P450 microsomal monooxygenases, were assayed in 2- and 12-month-old rats. Samples of blood and liver were obtained from controls (injected at 0 h with 0.5 ml of 0.9% NaCl) and at 12, 24, 48, 72 and 96 h of thioacetamide intoxication either to non-treated or phenobarbital pretreated rats. Potentiation of thioacetamide hepatotoxicity by phenobarbital pretreatment was demonstrated at morphological level, and by significant increases in the activities of serum aspartate aminotransferase and gamma-glutamyl transferase, and in the levels of total bilirubin. The extent of potentiation of thioacetamide-induced liver injury by phenobarbital pretreatment was similar in both age groups. Microsomal FAD monooxygenase activity, the enzyme responsible for thioacetamide biotransformation, was significantly enhanced (twofold) by phenobarbital pretreatment, and also underwent a further increase following thioacetamide, preceding the peak of necrosis. Cytochrome P450 monooxygenases were induced by phenobarbital pretreatment more than sixfold, and sharply decreased when phenobarbital was withdrawn and thioacetamide administered, showing at 48 h intoxication values close to basal. Phenobarbital pretreatment potentiated thioacetamide necrogenicity, and this potentiation was parallel to the induction of the microsomal FAD monooxygenase system, both by phenobarbital and by thioacetamide itself. The extent of thioacetamide-induced liver injury was significantly higher in 12-month-old rats, but the effect of phenobarbital pretreatment was similar in both age groups.
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PMID:Potentiation of thioacetamide hepatotoxicity by phenobarbital pretreatment in rats. Inducibility of FAD monooxygenase system and age effect. 1067 Aug 21

Effects of thioacetamide on antibody response to sheep red blood cells were investigated in male BALB/c mice. When mice were treated intraperitoneally with thioacetamide once, the antibody response was significantly suppressed at 200 mg/kg with hepatotoxicity. When mice were treated intraperitoneally with thioacetamide for 7 consecutive days, the antibody response was suppressed at 50 mg/kg without hepatotoxicity. To determine the possible role of metabolic activation by cytochrome P450 in thioacetamide-induced suppression of antibody response, mice were pretreated with phenobarbital intraperitoneally for 3 days, followed by intraperitoneal administration of 100 mg/kg of thioacetamide for 3 days. The elevated activities of serum aspartate aminotransferase and alanine aminotransferase by thioacetamide were potentiated by phenobarbital pretreatment. The suppression of antibody response by thioacetamide was potentiated by phenobarbital. In liver microsomes, the activities of P450 2B-specific enzymes were induced by phenobarbital. Our present results suggest that thioacetamide may require metabolic activation by P450 to its immunosuppressive form(s).
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PMID:Role of metabolic activation by cytochrome P450 in thioacetamide-induced suppression of antibody response in male BALB/c mice. 1071 88

The pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybip henyl-2-carboxylic acid-2'-carboxylate monohydrochloride (DDB-S) have been investigated in rats with CCl4-induced acute hepatic failure. To study the pharmacokinetics of DDB-S, rats were divided into a control group and a CCl4-intoxicated group. DDB-S 50 mg kg(-1) was administered by intravenous bolus injection to both groups of rats. In the CCl4-intoxicated rats the plasma concentrations of DDB-S were significantly higher, the area under the plasma concentration-time curve from time zero to time infinity was significantly greater (6-46 vs 3.34 mg min mL(-1)), and the total body (7.74 vs 15.0 mL min(-1) kg(-1)), renal (2.55 vs 5.10 mL min(-1) kg(-1)), nonrenal (5.07 vs 9.65 mL min(-1) kg(-1)), and biliary (1.48 vs 2.69 mL min(-1) kg(-1)) clearances were significantly slower compared with the control rats. This could be due to decreased hepatic cytochrome P450 activity and impaired kidney function induced by CCl4. To study the hepatoprotective effects of DDB-S, rats were divided into three groups, control rats and CCl4-intoxicated rats with or without DDB-S pretreatment (50 mg kg(-1) i.p.). The effects of DDB-S pretreatment on CCl4-induced liver injury were considerable; the serum levels of alanine transaminase, aspartate transaminase, and alkaline phosphatase were significantly lower by 54.3, 44.6 and 67.2%, respectively, compared with the CCl4-intoxicated-only group. In an in-vitro study, rat hepatocytes were exposed to fresh medium containing 10 mM CCl4 and various concentrations of DDB-S (10 or 100 microg mL(-1)). The levels of alanine transaminase and aspartate transaminase in the medium were measured as an indicator of hepatocyte injury. DDB-S dose-dependently decreased the levels of alanine transaminase and aspartate transaminase compared with CCl4-intoxication only. These results indicate that DDB-S has hepatoprotective activity.
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PMID:Pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4'-dimethoxy-5 ,6,5',6'dimethylenedioxybiphenyl-2-carboxylic acid-2'-carboxylate monohydrochloride in rats with CCl4-induced acute hepatic failure. 1104 90

Cypermethrin at different concentrations (100, 200, 400 and 800 ng ml(-1)) was incubated with a primary culture of rat hepatocytes. Cypermethrin was cytotoxic to rat hepatocytes at concentrations of 200 ng ml(-1)or greater. Toxicity was measured by a decrease in cell viability and leakage of ALT and AST enzymes into the culture medium. The role of cytochrome P450 in the hepatotoxicity of cypermethrin insecticide was investigated in fresh hepatocytes isolated either from phenobarbital pretreated rats or control rats and coincubated with SKF525A. Pretreatment with phenobarbital strongly protected the hepatocytes against the cypermethrin induced loss of cell viability percentage and increased enzyme leakage percentage. Coincubation of the hepatocytes with SKF525A, a well-known cytochrome P450 inhibitor, substantially potentiated the effect of cypermethrin on cell viability and enzyme leakage. These results suggest that the cytocidal hepatotoxicity of cypermethrin in primary hepatocyte culture depends on its parent compound and phenobarbital, as a cytochrome P450 inducer, could be of therapeutic value.
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PMID:The role of enzyme induction and inhibition on cypermethrin hepatotoxicity. 1142 8

The protective effects of an aqueous extract from the roots of Platycodon grandiflorum A. DC (Campanulaceae), Changkil (CK), on acetaminophen (APAP)-induced hepatotoxicities and the possible protective mechanisms involved were investigated in mice. Pretreatment with CK prior to the administration of APAP significantly prevented the increase in serum alanine aminotransferase and aspartate aminotransferase activity and hepatic lipid peroxidation in a dose-dependent manner. APAP-induced hepatotoxicity was also essentially prevented as evidenced by liver histopathology. Hepatic glutathione levels and glutathione-S-transferase activities were not affected by treatment with CK alone, but pretreatment with CK protected the APAP-induced depletion of hepatic glutathione levels. The effects of CK on cytochrome P450 (P450) 1A2 and 2E1, the major isozymes involved in APAP bioactivation, were investigated. In microsomal incubations, CK effectively inhibited P450 lA2-dependent methoxyresorufin O-deethylase activities and the P450 2E1-dependent p-nitrophenol and aniline hydroxylase. The results suggest that the protective effects of CK against the APAP-induced hepatotoxicity may, at least in part, be due to its ability to block P450-mediated APAP bioactivation.
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PMID:Hepatoprotective effects of Platycodon grandiflorum on acetaminophen-induced liver damage in mice. 1167 54

The protective effects of a Platycodi radix (Changkil: CK), the root of Platycodon grandiflorum A. DC (Campanulaceae) on carbon tetrachloride (CC14)-induced hepatotoxicity and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with CK prior to the administration of CC14 significantly prevented the increased serum enzymatic activities of alanine and aspartate aminotransferase in a dose-dependent manner. In addition, pretreatment with CK also significantly prevented the elevation of hepatic malondialdehyde formation and the depletion of reduced glutathione content in the liver of CC14-intoxicated mice. However, hepatic reduced glutathione levels and glutathione S-transferase activities were not affected by treatment with CK alone. CC14-induced hepatotoxicity was also essentially prevented, as indicated by a liver histopathologic study. The effects of CK on the cytochrome P450 (P450) 2E1, the major isozyme involved in CC14 bioactivation were also investigated. Treatment of mice with CK resulted in a significant decrease of P450 2E1-dependent p-nitrophenol and aniline hydroxylation in a dose-dependent manner. CK showed antioxidant effects in FeCl2-ascorbate-induced lipid peroxidation in mice liver homogenate and in superoxide radical scavenging activity. Our results suggest that the protective effects of CK against CC14-induced hepatotoxicity possibly involve mechanisms related to its ability to block P450-mediated CC14 bioactivation and free radical scavenging effects.
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PMID:Protective effect of Platycodi radix on carbon tetrachloride-induced hepatotoxicity. 1189 10


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