Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intoxication of male and female mice with a single dose (300 or 600 mg/kg) of 1,1,2,2-tetrachloroethane (TTCE) resulted in significant decreases in cytochrome P-450 (to 58-73% of the control) and NADPH-cytochrome (P-450) c-reductase (to 29-35% of the control) in hepatic microsomes. This was accompanied by an alteration of mixed function monooxygenases stemming from the marked reduction (to 20-64% of the control) of several oxidative activities to selected substrates towards different P-450 isozymes (classes IA1, IA2, IIB1, IIE1 and IIIA). As phase II markers, epoxide hydrolase (approximately 35% loss), UDP-glucuronosyl transferase (approximately 42% loss) and to a lesser extent glutathione S-transferase (approximately 17% loss) were all affected. Also, the activity of delta-aminolevulinic (ALA) synthetase was decreased (approximately 57% of the control). On the contrary, heme oxygenase activity was increased (up to 35%) at the maximal dose tested. The decrease of P-450-function may be explained in terms of an alteration in the rate of heme biosynthesis and degradation, provoking a loss of heme content (approximately 33%) as well as of the direct inactivation of both P-450 and reductase. Because of increasing evidence on the involvement of free radical intermediates in the case of toxicity of haloalkanes, electron spin resonance spectroscopy (ESR) spin-trapping in vivo techniques were used to characterize the possible free radical species involved in the observed liver damage. The results obtained with the spin-trap N-benzylidene-2-methylpropylamine N-oxide (phenyl t-butylnitrone, PBN) provide evidence for the formation and trapping of the CHCl2CHCl free radicals. The detection of conjugated diene signals by means of second-derivative spectrophotometry, have enabled us to show that in vivo lipid peroxidation may be one of the main mechanisms responsible for TTCE hepatotoxicity.
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PMID:On the hepatotoxicity of 1,1,2,2-tetrachloroethane. 131 68

The mechanism of DDB (dimethyl 4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy biphenyl-2,2'-dicarboxylate) prevention of aflatoxin B1 (AFB1)-induced hepatotoxicity in rats has been investigated. Pretreatment of DDB (200 mg/kg) daily for 4 days significantly suppressed (P < 0.05) the AFB1-induced hepatic damage as evidenced by the increase of serum marker enzymes. DDB induced rat hepatic cytochrome P450IA1, IIB1 and glutathione S-transferase activities. The hepatic microsomes derived from DDB treated rats increased the mutation frequency of AFB1 and enhanced the binding of AFB1 to DNA. However, the hepatic S9 fraction from DDB treated rats showed a protective effect against AFB1-induced damage. It is concluded that the protective effect of DDB against AFB1-induced damage might be mediated by the induced glutathione S-transferase activity and not from the accelerated hepatic cytochrome P450 detoxification pathway of AFB1 which was previously believed.
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PMID:Mechanistic study of the inhibition of aflatoxin b1-induced hepatotoxicity by dimethyl 4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy biphenyl-2, 2'-dicarboxylate. 788 30

Hepatic cytochrome P-450 activity has been shown to be affected by various dietary factors including vitamin E. However, reports of the effect of dietary vitamin E on cytochrome P-450 activity have been inconsistent. The aim of the present study was to investigate the influence of dietary vitamin E on rat hepatic cytochrome P-450 activity. Three groups of six male weanling Sprague-Dawley rats were fed semipurified diets containing 0, 100, or 1,500 ppm vitamin E for eight weeks. Vitamin E was given in the form of alpha-tocopheryl acetate. Dietary vitamin E significantly affected liver vitamin E content (p < 0.05) but had no effect on rat hepatic total P-450 content, N-nitrosodimethylamine demethylase, and NADPH-cytochrome-P-450 reductase activities. Hepatic pentoxyresorufin O-dealkylase and glutathione S-transferase activities were significantly greater in rats fed 100 and 1,500 ppm vitamin E than in rats fed no vitamin E (p < 0.05). Dietary vitamin E induced changes in hepatic phospholipid fatty acid composition. Hepatic phospholipid linoleate was significantly greater in rats fed 0 and 1,500 ppm vitamin E than in rats fed 100 ppm vitamin E (p < 0.05). Hepatic phospholipid eicosapentaenoate was increased significantly by dietary vitamin E (p < 0.05). Hepatic thiobarbituric acid-reactive substance was significantly greater in rats fed no vitamin E than in rats fed 100 and 1,500 ppm vitamin E (p < 0.05). The results suggest that vitamin E may influence cytochrome P-450 IIB1 enzyme activity and may affect hepatic phospholipid fatty acid composition.
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PMID:Effect of vitamin E on rat hepatic cytochrome P-450 activity. 979 69

While cancer drug resistance has been extensively studied in cell culture, little is known about more clinically relevant in vivo resistance. The in vivo resistance of a murine mammary carcinoma EMT-6 to alkylating agents was demonstrated in the present study to be associated with multiple biochemical changes. These included an up to 1.5-fold increase in activity of phase II drug metabolizing enzymes (DMEs), such as glutathione (GSH), glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPX) and aldehyde dehydrogenase (ALDH), and an up to 88% decrease of phase I DME activity [7-ethoxycumarin O-deethylase (ECOD), P450 reductase (PR)] in the resistant tumors compared with the parental tumor. Transplant of either parental or resistant tumors to mice was accompanied by a decrease of both phase I and phase II DME activity in the livers of female Balb/C mice compared with the non-tumor mice. Moreover, at the protein level, while cytochrome P450 (CYP) IIB1/2 in the liver of mouse bearing both the sensitive and the resistant tumor was significantly diminished compared to that in the liver of non-tumor control mouse in Western analysis, there was actually an increase of this protein in the liver of the host bearing either of the two resistant tumors compared to that of the sensitive tumor-bearing animal. Although this in vivo resistance phenotype is not expressed in cell culture, the profile of most of the enzyme changes in the resistant tumors remained similar in in vitro culture of the isolated tumor cells. Collectively, these results demonstrate that this in vivo alkylating agent resistance is associated with multiple changes of both phase I and phase II DMEs in the resistant tumors, and some of these, such as CYP IIB1/2 protein are further altered in the resistant tumor-bearing mouse liver, suggesting a potential role of systemic factors in this resistance phenotype.
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PMID:Biochemical characterization of in vivo alkylating agent resistance of a murine EMT-6 mammary carcinoma. Implication for systemic involvement in the resistance phenotype. 992 73

After 6 days following the local effect (during operation) of ultrasound (2 Wt/cm2, 1 min) the microsomal fraction showed decreased total content of cytochromes P-450 (P-450), rate of NADPH oxidation, activity of NADPH-cytochrome P450 reductase and P450 IIE1 (aniline as substrate) by 40, 28, 16 and 42 %, respectively. In addition, after 12 days the activities of P450 IIIA1 (ethylmorphine as substrate) and cytosolic sulphobromophthalein glutathione transferase (SBPh-GT) were decreased by 59 and 26 %. The administration of heparin (intramuscularly, 250 ED/kg, in a day, 3 and 6 times) exerted a normalizing effect. The P450 concentration, NADPH oxidation rate and P450 IIB1 activity (amidopyrine as substrate), IIE1 and IIIA1, SBPh-GT and 1-chloro-2,4-dinitrobenzene-GT in microsomes and cytosol exceeded the corresponding values in untreated animals by 31, 40, 68, 224, 68, 42, 24 and 36 %. The administration of heparin to control animals (intramuscularly, 250 and 500 mg/kg, in a day, 5 times) essentially unaffected both the monooxygenase, glucuro- and glutathione-conjugating systems and the elimination of antipyrine (substrate of preferably P-450 IA2) and SBPh (substrate of GT) from rat blood plasma. The experimental results provide evidence for a possible role of endogenous heparin in maintaing the optimal level of the activities of the enzyme systems of xenobiotics microsomal oxidation and conjugation in liver injury. One of the most important functions of the liver is its ability to execute biotransformation of a wide range of xenobiotics and some endogenous substances [1]. The activities of the enzyme systems catalyzing these reactions are under a sophisticated regulatory control. Among the natural factors capable of changing the function of enzymes involved in the xenobiotic biotransformation are vitamins [2], phospholipids [3], hormones [4] and many others. We studied the effect of heparin on the activities of the monooxygenase, glucuro- and glutathione transferase systems of the intact and ultrasound-treated rat liver. The significance of this study consists in the elucidation of a putative participation of heparin in the control of the activities of the enzyme system of xenobiotic biotransformation in the intact liver and under membranous pathology of the organ.
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PMID:Inhibition of enzymes of drug metabolism in rat liver by ultrasound and correction by heparin. 1044 98