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)

2-(Allylthio)pyrazine (2-AP), a synthetic organosulfur compound, exhibits hepatoprotective and chemopreventive effects. The effects of 2-AP on aflatoxin B1 (AFB1)-induced hepatotoxicity was studied in rats. 2-AP treatment substantially reduced AFB1-induced toxicity, as evidenced by reduction in the mortality rate of animals as well as decreases in serum alanine aminotransferase and sorbitol dehydrogenase activities. AFB -induced lipid peroxidation was also significantly reduced in rats by 2-AP treatment. Studies were extended to determine whether 2-AP was active in inhibiting cytochrome P450-mediated metabolic activation of AFB1. Covalent binding of AFB1 to calf thymus DNA in the presence of S-9 fraction was inhibited by 2-AP in vitro. Hepatic microsomal pentoxyresorufin-O-depentylase and ethoxyresorufin-O-deethylase activities were also potently inhibited by 2-AP. These results demonstrated that 2-AP was effective in protecting the liver against AFB1-induced toxicity and the mechanism of chemoprotection by 2-AP might involve inhibition of the P450 2B- and 3A2-mediated metabolism of AFB1.
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PMID:2-(allylthio)pyrazine inhibition of aflatoxin B1-induced hepatotoxicity in rats: inhibition of cytochrome P450 2B- and 3A2-mediated bioactivation. 992 Mar 47

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

The protective effects of oleanolic acid on carbon tetrachloride-induced hepatotoxicities and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with oleanolic acid prior to the administration of carbon tetrachloride significantly prevented the increase in serum alanine aminotransferase and lactate dehydrogenase activity and liver lipid peroxidation in a dose-dependent manner. Hepatic glutathione levels and glutathione-S-transferase activities were not affected by treatment with oleanolic acid alone but pretreatment with oleanolic acid protects carbon tetrachloride-induced depletion of hepatic glutathione levels. The effects of oleanolic acid on the cytochrome P450 (P450) 2E1, the major isozyme involved in carbon tetrachloride bioactivation were investigated. Treatment of mice with oleanolic acid resulted in a significant decrease of P450 2E1-dependent p-nitrophenol and aniline hydroxylation in a dose-dependent manner. Consistent with these observations, the P450 2E1 expressions were also decreased, as determined by immunoblot analysis. These results show that the protective effects of oleanolic acid against the carbon tetrachloride-induced hepatotoxicity may, at least in part, be due to its ability to block bioactivation of carbon tetrachloride mainly by the inhibition of expression and activities of P450 2E1.
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PMID:Inhibition of cytochrome P450 2E1 expression by oleanolic acid: hepatoprotective effects against carbon tetrachloride-induced hepatic injury. 1035 42

Precision-cut liver slices from phenobarbital-induced rats were incubated for 6 h with the model hepatotoxin bromobenzene (BB) at a final concentration of 1 mM. Severe toxicity was indicated by a decreased K+, adenosine triphosphate and glutathione (GSH) content of the slices, increased release of alanine aminotransferase and lactate dehydrogenase into the medium, and increased formation of thiobarbituric acid reacting substances. Pretreatment of animals for 7 days with aged garlic extract (AGE) (Kyolic) at doses of 2 and 10 ml/kg/day dramatically reduced the toxicity of BB in a dose-dependent manner. The GSH content of liver slices from rats treated with AGE at 2 or 10 ml/kg/day increased by 50 and 80%, respectively. The BB-induced decrease in GSH content was less in slices derived from AGE-treated rats compared with slices from control rats. Pretreatment with AGE did not affect cytochrome P450 when assayed as 7-ethoxycoumarin O-deethylase and 7-pentoxyresorufin O-depentylase activities in hepatic microsomes. Thus, the mechanism by which pretreatment with AGE protects against BB hepatotoxicity involves both an elevation of hepatic GSH content, and a GSH sparing effect, possibly due to conjugation of organosulphur compounds in AGE with toxic BB metabolites. Only this GSH sparing effect was seen in our earlier study on the in vitro hepatoprotective effect of AGE [Wang et al., 1998. Toxicology 126, 213-222].
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PMID:Treatment with aged garlic extract protects against bromobenzene toxicity to precision cut rat liver slices. 1043 84

The safety and tolerability of quinupristin/dalfopristin were assessed in both comparative and non-comparative trials (2298 quinupristin/dalfopristin-treated patients). In comparative clinical trials, the most frequent systemic adverse events related to quinupristin/dalfopristin were nausea (4.6%), diarrhoea (2.7%), vomiting (2.7%) and skin rash (2.5%). The comparator group showed similar rates, except that nausea was significantly more common (7.2%; P = 0.01). In non-comparative trials, arthralgia and myalgia were reported most frequently but were reversible upon treatment discontinuation. The renal, inner ear, cardiovascular and central nervous systems were not implicated as significant target organs for toxicity. The most frequent local adverse events related to infusion of quinupristin/dalfopristin were inflammation, pain, oedema, infusion site reaction and thrombophlebitis. Results of laboratory tests while on therapy were comparable for quinupristin/dalfopristin and comparator groups, except that increases in conjugated bilirubin of >5 x the upper limit of normal were reported in 5.5% of quinupristin/dalfopristin recipients; increases in total bilirubin of >5 x the upper limit of normal occurred in 1.5%. Comparator recipients more frequently had increases in alanine aminotransferase and alkaline phosphatase. Quinupristin/dalfopristin inhibits the cytochrome P450 3A4-mediated metabolism of drugs including midazolam, nifedipine, terfenadine and cyclosporin. Therefore, plasma drug monitoring and/or dosage reduction of these agents is prudent. Concomitant administration of drugs that can prolong the electrocardiographic QTc interval should be avoided. Quinupristin/dalfopristin is visually and chemically compatible with commonly used drugs of various classes, but it is not compatible with sodium chloride solution and certain other drugs, including some antimicrobials. Therefore, when prescribing quinupristin/dalfopristin, clinicians should be aware of the potential for peripheral venous intolerance, arthralgias and myalgias, increases in conjugated bilirubin, interactions with drugs metabolized by the cytochrome P450 3A4 isoenzyme and certain physico-chemical incompatibilities. However, multiple studies have shown that the safety and tolerability of quinupristin/dalfopristin are generally favourable, and that it provides clear benefits to ill patients with severe gram-positive infections.
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PMID:Safety and tolerability of quinupristin/dalfopristin: administration guidelines. 1051 96

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

Mice were fed with high zinc diet (15 g/kg) for 3 weeks. High zinc could cause liver toxicity: 1. inhibiting the activity of GOT and GPT in liver homogenate, reducing GSH and glycogen contents. 2. increasing the activity of aniline hydroxylase and inhibiting the activities of NADPH-cytochrome C reducease, benzo-phytamine-N-demethylase and glutathione S-transferase. The activities of cytochrome P450 and cytochrome b5 were not obviously changed 3. increasing microsomal membrane fluidity in the superficial layers, but not in the deep layers.
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PMID:[Effects of high dietary zinc on liver function, hepatic drug metabolism enzymes and membrane fluidity in mice]. 1068 26

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

Reductive metabolism of halothane in phenobarbital-pretreated rats is known to increase free radical formation that results in hepatotoxicity. It also is associated with a marked induction of microsomal heme oxygenase-1 (HO-1), suggesting that there is an alteration in heme metabolism. In this study, we examined heme metabolism in rats pretreated with phenobarbital, followed by exposure to halothane-hypoxia. In this model, there was a significant decrease in microsomal cytochrome P450 content in the liver, followed by a rapid increase in free heme concentration and a decrease in the level of mRNA for the nonspecific delta-aminolevulinate synthase. A transient but dramatic induction of HO-1 mRNA and a prolonged induction of heat shock protein 70 mRNA also occurred. The HO-1 protein was detected principally in the hepatocytes around the central vein. Serum alanine transaminase (ALT) activity, an indicator of hepatic dysfunction, increased continuously throughout the experiment. Hemin pretreatment induced hepatic HO-1 with abrogation of the halothane-induced hepatotoxicity in this model, as judged by ALT activity and normal histology. Our findings in this study thus indicate that halothane-induced hepatotoxicity is due not only to its reductive metabolite formation, but also to an increase in hepatic free heme concentration, which is a potent prooxidant; HO-1 induction is an important protective response against such changes. This is also the first study to demonstrate that hemin pretreatment, which induces HO-1 prior to exposure to halothane, effectively prevents halothane-induced hepatotoxicity.
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PMID:Prevention of halothane-induced hepatotoxicity by hemin pretreatment: protective role of heme oxygenase-1 induction. 1071 46


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