Potency of isothiocyanates to induce luciferase reporter gene expression via the electrophile-responsive element from murine glutathione S-transferase Ya

Isothiocyanates are electrophiles that are able to induce phase II biotransformation enzyme gene expression via an electrophile-responsive element (EpRE) in the gene regulatory region. To study the potency of different isothiocyanates to induce the expression of EpRE-regulated genes, a Hepa-1c1c7 luciferase reporter cell line was exposed to...

Polymorphisms in genes related to activation or detoxification of carcinogens might interact with smoking to increase renal cancer risk: Results from The Netherlands Cohort Study on diet and cancer

Metabolic gene polymorphisms have previously been suggested as risk factors for renal cell carcinoma (RCC). These polymorphisms are involved in activation or detoxification of carcinogens in cigarette smoke which is another RCC risk factor. We evaluated gene-environment interactions between CYP1A1, GSTμ1 and smoking in a large population-based...

Structural requirements for the flavonoid-mediated modulation of glutathione S-transferase P1-1 and GS-X pump activity in MCF7 breast cancer cells

The objective of this study was to investigate the structural requirements necessary for inhibition of glutathione S-transferase P1-1 (GSTP1-1) and GS-X pump (MRP1 and MRP2) activity by structurally related flavonoids, in GSTP1-1 transfected MCF7 cells (pMTG5). The results reveal that GSTP1-1 activity in MCF7 pMTG5 cells can be inhibited by some...

Inhibition of human glutathione S-transferase P1-1 by the flavonoid quercetin

In the present study, the inhibition of human glutathione S-transferase P1-1 (GSTP1-1) by the flavonoid quercetin has been investigated. The results show a time- and concentration-dependent inhibition of GSTP1-1 by quercetin. GSTP1-1 activity is completely inhibited upon 1 h incubation with 100 μM quercetin or 2 h incubation with 25 μM quercetin...

Biological monitoring the exposure to polycyclic aromatic hydrocarbons of coke oven workers in relation to smoking and genetic polymorphisms for GSTM1 GSTT1

Occupational exposure to polycyclic aromatic hydrocarbons (PAH) increases the risk of developing lung cancer. Human exposure is often demonstrated by increased internal levels of PAH metabolites and of markers for early biological effects, like DNA adducts and cytogenetic aberrations. Objective: This study aimed to assess whether the current...

The interplay of glutathione-related processes in antioxidant defense

This review summarizes current knowledge on glutathione (GSH) associated cellular processes that play a central role in defense against oxidative stress. GSH itself is a critical factor in maintaining the cellular redox balance and has been demonstrated to be involved in regulation of cell signalling and repair pathways. Enhanced expression of...

A physiologically-based pharmacokinetic (PB-PK) model for ethylene dibromide: Relevance of extrahepatic metabolism

A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new data were used for the human class ΘGST T1-1....

Glutathione conjugation as a bioactivation reaction

In general, glutathione conjugation is regarded as a detoxication reaction. However, depending on the properties of the substrate, bioactivation is also possible. Four types of activation reaction have been recognized: direct-acting compounds, conjugates that are activated through cysteine conjugate beta-lyase, conjugates that are activated...

Interactions of prostaglandin A2 with the glutathione-mediated biotransformation system

The cyclopentenone prostaglandin A2 (PGA2) is known to inhibit cell proliferation, and metabolism of this compound thus might be important in controlling its ultimate function. The glutathione-related metabolism of PGA2 was therefore investigated both with purified glutathione S-transferase P1-1 (GSTP1-1) and with IGR-39 human melanoma cells....

Conjugation of isoprene monoepoxides with glutathione, catalyzed by α, μ, π and θ-class glutathione S-transferases of rat and man

In the present study, the enzymatic conjugation of the isoprene monoepoxides 3,4 epoxy-3-methyl-1-butene (EPOX-I) and 3,4-epoxy-2-methyl-1-butene (EPOX-II) with glutathione was investigated, using purified glutathione S-transferases (GSTs) of the α, μ, π and θ-class of rat and man. HPLC analysis of incubations of EPOX-I and EPOX-II with [35S...

Selection of Arabidopsis mutants overexpressing genes driven by the promoter of an auxin-inducible glutathione S-transferase gene

Transgenic arabidopsis plants were isolated that contained a T-DNA construct in which the promoter of an auxin-inducible glutathione S-transferase (GST) gene from tobacco was fused to the kanamycin resistance (nptII) as well as to the β-glucuronidase (gusA) reporter gene. Subsequently, seeds were treated with EMS to obtain mutants in which both...

Role of glutathione, glutathione S-transferases and multidrug resistance-related proteins in cisplatin sensitivity of head and neck cancer cell lines

Resistance to chemotherapy is a major problem in the treatment of patients with head and neck squamous cell carcinoma (HNSCC). Important factors involved are drug detoxification by glutathione (GSH) and reduced drug accumulation due to active transport out of the cell by so-called 'multidrug resistance-related proteins'. We have studied a panel...

GSTP1-1 stereospecifically catalyzes glutathione conjugation of ethacrynic acid

Using 1H NMR two diastereoisomers of the ethacrynic acid glutathione conjugate (EASG) as well as ethacrynic acid (EA) could be distinguished and quantified individually. Chemically prepared EASG consists of equal amounts of both diastereoisomers. GSTP1-1 stereospecifically catalyzes formation of one of the diastereoisomers (A). The GSTP1-1...

In vitro inhibition of rat and human glutathione S-transferase isoenzymes by disulfiram and diethyldithiocarbamate

The drug disulfiram (DSF, Antabuse®) has been used in the therapy of alcohol abuse. It is a potent inhibitor of aldehyde dehydrogenase. Its reduced form, diethyldithiocarbamate (DDTC), and further metabolites show similar activities. DSF and DDTC have also been widely used to inhibit mixed-function oxidases. In this study, the reversible...

Inhibition of glutathione S-transferase activity in human melanoma cells by alfa, beta-unsaturated carbonyl derivatives: Effects of acrolein, cinnamaldehyde, citral, crotonaldehyde, curcumin, ethacrynic acid, and trans-2-hexenal

The glutathione S-transferase (GST) activity towards 1-chloro-2,4-dinitrobenzene in intact human IGR-39 melanoma cells was determined by the quantification by HPLC-analysis of the excreted glutathione (GSH) conjugate (S-(2,4-dinitrophenyl)glutathione; DNPSG). The major GST subunit expressed in these melanoma cells is the π-class GST subunit P1....