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:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hexachlorobenzene (HCB) was administered orally (500 mg/kg d) for 1, 2, 5, or 10d) to sexually mature Japanese quail to compare altered hepatic porphyrin levels with changes that occur in hepatic xenobiotic metabolizing enzymes. Porphyrin levels rapidly increased following the administration of HCB (three times control levels after a single dose of HCB), and birds began to develop porphyria (i.e., porphyrin levels were at least 10 times higher than controls) following 5 d of treatment. Following 10 d of HCB treatment, 3 of 4 treated quail were porphyric. Coincident with the HCB-induced disruption of the heme biosynthetic pathway were increases in various hepatic constituents. Changes included elevation of microsomal protein concentrations and increases in the specific content of cytochrome P-450, in the activities of aryl hydrocarbon hydroxylase (AHH), biphenyl hydroxylase (BPH), ethoxyresorufin-O-deethylase (EROD), and ethoxycoumarin-O-deethylase (ECOD), and in cytosolic and microsomal glutathione S-transferase (GSH-t) levels. In addition, the lambda max of the CO versus CO-reduced absorption spectra of hepatic microsomes from HCB-dosed birds showed a hypsochromic shift of 450 to 448 nm. The activity of NADPH-cytochrome P-450 reductase was increased following 10 d of HCB, and the activity of epoxide hydrolase was increased following 5 d of HCB. Most of these changes occurred with a single HCB treatment, and no further alterations developed in the nature of the response with repetitive dosing. Only weight loss, increased cytochrome P-450 content, and increases in GSH-t activity occurred simultaneously with the induction of porphyria.
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PMID:Hexachlorobenzene-induced porphyria in Japanese quail: changes in microsomal enzymes. 403 90

In an effort to determine the role that metabolism by the cytochrome P-450 system plays in the development of hexachlorobenzene (HCB)-induced porphyria, Japanese quail were pretreated with either beta-naphthoflavone (BNF) or phenobarbital (PB) and then treated with HCB. PB or BNF pretreatment appeared to have no effect on the response of quail hepatic enzymes to HCB. There were no differences between the two groups in either the content of cytochrome P-450 or the activities of NADPH-cytochrome c reductase, glutathione transferase (microsomal or cytosolic), ethoxycoumarin-O-deethylase or ethoxyresorufin-O-deethylase following HCB treatment. These pretreatments did, however, markedly influence the development of porphyria in quail. BNF-treated birds had higher delta-aminolevulinic acid-synthetase (ALA-S) activities and developed porphyria much more rapidly than birds treated with HCB alone. Birds pretreated with PB did not exhibit porphyria even following 10 days of HCB. Although the ALA-S activities in this group were elevated slightly following HCB, they were about one-half of those seen in the BNF-pretreated HCB-treated group. These results may reflect a difference between the PB and BNF groups in the production of a porphyrogenic metabolite of HCB.
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PMID:Hexachlorobenzene-induced porphyria in Japanese quail. Effect of pretreatment with phenobarbital or beta-naphthoflavone. 643 14

The porphyrinogenic action of 1,2,4-trichlorobenzene (TCB) was examined in 17-day-old embryos, day-old chicks, 18-day-old chickens and adult Japanese quail. The quail was found to be the most sensitive species towards TCB induced porphyria whereas the chick embryo was totally non-responsive. The liver porphyrins of Japanese quail were increased in a dose-dependent manner 1 day after TCB. Elevation in porphyrin levels in quail was associated with comparable increases in delta-aminolevulinic acid synthetase (ALA-S) activity 1 day after TCB treatment. In contrast, ferrochelatase activity was found to be unchanged 1 day after TCB. Multiple administration of TCB produced only a slight increase in liver porphyrin levels and ALA-S activity in quail. However, there was a marked induction in ferrochelatase activity suggesting increased porphyrin turnover. Liver glutathione and glutathione S-transferase activity were also significantly increased following repeated administration of TCB in quail, which could indicate an enhancement of detoxication of reactive metabolites of TCB. Thus, it is suggested that the inability of low multiple doses of TCB to cause porphyria in Japanese quail may be related to the low responsiveness of ALA-S but high inducibility of ferrochelatase liver GSH and glutathione S-transferase.
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PMID:Studies on the porphyrinogenic action of 1,2,4-trichlorobenzene in birds. 663 2

Exposure of iron-loaded C57BL/10ScSn mice to the polychlorinated biphenyls (PCBs) mixture Aroclor 1254 in the diet (0.01%) for 5 weeks caused massive hepatic porphyria far greater than occurred with PCBs alone. This regime eventually causes hepatocellular carcinoma. Hepatic microsomal ethoxy-, pentoxy-, and benzyloxyresorufin dealkylase activities (respectively EROD, PROD, and BROD) catalyzed primarily by cytochrome P4501A1 and 2B isoenzymes were markedly induced after 2 weeks of diet (when no porphyria had developed) but showed little effect of iron. EROD activity in the nuclear membrane was also induced by the PCBs as was CYP1A1 protein when shown by immunoblotting. Nuclear dealkylase activities of PCBs-treated mice were considerably less than microsomal activities but were stimulated by iron pretreatment. The mechanism of the iron-enhanced toxicity may be due to oxidative damage associated with chronic induction of CYP1A1 isoforms. Lucigenin-enhanced chemiluminescence (CL) by microsomes and nuclear membranes was used as a method to estimate their potential to form reactive oxygen species. Despite CL being induced by PCBs it was less with microsomes from iron-treated mice. In a comparison of a variety of inducers of microsomal cytochrome P450 there was no correlation between inducer, uroporphyrogenic agent, and intensity of CL. On the other hand, cytosolic glutathione S-transferase (GST) activities with 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene (DCNB) as substrates, were also induced by the PCBs mixture, the induction with DCNB being synergistically potentiated by iron pretreatment. Complementary results were observed by immunocytochemistry using anti alpha-GST antibody. In contrast, total glutathione peroxidase activity and selenium-dependent glutathione peroxidase activity were depressed by PCBs but particularly in mice also administered iron. The results illustrate that PCBs not only induce CYP1A1 in microsomes but also in the nuclear membrane, which may be of significance in the mechanism of the iron-enhanced carcinogenicity of these chemicals. The iron-enhanced induction of GST with accompanying depletion of glutathione peroxidase provides evidence for oxidative processes induced in vivo by the PCBs.
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PMID:Modulation by iron of hepatic microsomal and nuclear cytochrome P450, and cytosolic glutathione S-transferase and peroxidase in C57BL/10ScSn mice induced with polychlorinated biphenyls (Aroclor 1254). 856 Apr 83

The binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with the aryl hydrocarbon (AH) receptor and subsequent changes in gene expression have been studied intensively, but the mechanisms by which these lead to toxicity are unclear. We investigated the influence of iron, previously implicated in TCDD-induced hepatic porphyria, in mice with alleles of Ahr that encode receptors with varied affinity for TCDD. The administration of iron to Ahrb-1 C57BL/6J (AH-responsive) mice before a single dose of TCDD (75 micrograms/kg) markedly potentiated not only the hepatic porphyria but also general hepatocellular damage and elevation of plasma hepatic enzymes. The formation of hydroxylated and peroxylated derivatives of uroporphyrins formed from uroporphyrinogen and the induction of a mu-glutathione transferase (GST) were consistent with the operation of an oxidative mechanism. In a comparison of C57BL/6J mice with Ahrb-2 BALB/c (AH-responsive) and Ahrd SWR and DBA/2 (AH-nonresponsive) mice, iron overcame the weak hepatic porphyria and toxicity responses in BALB/c and SWR strains but not in DBA/2. CYP1A isoforms are strongly implicated in the mechanism of porphyria, but activities were lowered by 20-30% with iron treatment, and a comparison of levels between strains did not fully account for the resistance of DBA/2 mice. Studies with the use of gel shift assays and cytosolic aconitase of the capacity of the iron regulatory protein controlling the translation of some iron metabolism proteins showed a significant difference between C57BL/6J and DBA/2 mice after the administration of TCDD. We conclude that iron potentiates both the hepatic porphyria and toxicity of TCDD in susceptible mice in an oxidative process with disturbance of iron regulatory protein capacity. Iron even overcomes the AH-nonresponsive Ahrd allele in the SWR strain but not in DBA/2 mice, which remain resistant.
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PMID:Interaction between iron metabolism and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice with variants of the Ahr gene: a hepatic oxidative mechanism. 944 32

Numerous minute milky white foci were distributed throughout the dark brown liver in an adult male fox squirrel. Histologically, the hepatic focal lesions were composed of large eosinophilic granular hepatocytes, which were mostly positive for glutathione S-transferase mu antigen and proliferating cell nuclear antigen. Electron microscopy demonstrated an increased number of mitochondria. These features corresponded to those in the eosinophilic type of foci of altered hepatocytes. Berlin blue stain showed severe haemosiderin deposition in hepatocytes, except in the focal lesions. Since the fox squirrel is known to be liable to develop congenital porphyria, it is suggested that the hepatic anomalies described may be closely associated with the development of porphyria.
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PMID:Foci of altered hepatocytes in a fox squirrel (Sciurus niger) with haemochromatosis. 1527 64

Porphyria cutanea tarda (PCT) is a cutaneous porphyria with sporadic (type 1) and familial (type 2) subtypes, both resulting from decreased hepatic uroporphyrinogen decarboxylase (UROD) activity. Environmental and genetic factors are involved in the development of PCT, and genetic variants in the cytochrome P450 (CYP ) genes, CYP1A1 and CYP1A2, have been implicated. We investigated the association between PCT and variants in CYP1A1, CYP1A2 and CYP2E1, and the glutathione-S-transferase (GST ) genes, GSTM1 and GSTT1. PCT diagnosis was based on urinary or plasma porphyrin profiles. Patients were classified as type 1 or 2 PCT based on UROD mutation analysis. The CYP1A2*1F promoter A allele frequency was significantly higher (P < 0.022) and the A/A genotype frequency marginally higher in PCT patients overall (P < 0.057), with the A/A genotype significantly more common in type 1 PCT (P < 0.043). The presence of the wild-type GSTM1 allele also was associated significantly with PCT (P < 0.019). Neither hemochromatosis (HFE) mutations, tobacco smoking, hepatitis C and HIV infection, ethanol consumption, nor estrogen use were associated with these allelic variants. Age at onset was significantly lower in type 2 PCT patients (P < 0.001), as observed previously. Thus, positive associations between PCT and the CYP1A2*1F promoter A allele and A/A genotype and the wild-type GSTM1 allele indicates that these functional hepatic biotransformation enzymes are risk factors for the development of this disease.
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PMID:CYP1A2*1F and GSTM1 alleles are associated with susceptibility to porphyria cutanea tarda. 2095 36

A classical acute porphyria model in rats consists of combined treatment with 2-allyl-2-isopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). The present work describes the effects of this treatment on the pentose phosphate (PP) pathway, glutahione metabolism and redox state and how they contribute to alter the glucose pool of hepatocytes and modulate porphyria, in Wistar rat livers. Our approach is based on the fact that glucose is a repressor of 5-aminolevulinic synthase (ALA-S), the rate-limiting enzyme of the heme pathway, and treatment with AIA/DCC causes oxidative stress. Different doses of the xenobiotcs were used. The results show that AIA (500 mg/kg body weight [BW])/DDC (50 mg/kg [BW]) treatment increased glutathione peroxidase (GPx) activity by 46%, decreased both glutathione reductase (GR) and glutathione S-transferase (GST) activity by 69% and 52%, respectively, and reduced by 51% reduced glutathione (GSH) and increased by 100% glutathione disulfide (GSSG) concentrations, therefore lowering by four-fold the GSH/GSSG ratio. The activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of PP-pathway, was increased by 129% as well as that of 6-phosphogluconate dehydrogenase. NADPH and the NADPH/NADP(+) ratio were increased by 14% and 28%, respectively. These effects could be attributed to the generation of reactive oxygen species (ROS) elicited by the porphyrinogenic treatment, shown by enhanced DNA damage and ROS production. G6PD stimulation would decrease hepatic glucose concentrations and consequently exacerbate the porphyria. A decrease in glucose could stimulate ALA-S and this would add to the effect of drug-induced heme depletion. Since the key role of GST is to inactivate toxic compounds, the drastic fall in its activity together with the accumulation of ALA would account for the symptoms of this hepatic disease model. The present findings show the high metabolic interplay between pathways and constitute a relevant contribution to achieve a better treatment of acute human porphyria.
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PMID:Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. Their impact on heme pathway. 2339 Jan 66

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