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At least 613 records · Page 34Linked to original sources
PubMed2003

Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB.

Many cancers have constitutively activated NFkappaB, the elevation of which contributes to cancer cell resistance to chemotherapeutic agent-induced apoptosis. Although mitogen-activated protein kinase/extracellular-regulated kinase kinase kinase-3 (MEKK3) has been shown to participate in the activation of NFkappaB, its relations to apoptosis and cancer are unclear. In this study, we established cell model systems to examine whether stable expression of MEKK3 could lead to increased NFkappaB activity and confer resistance to apoptosis. In addition, we investigated in breast and ovarian cancers whether MEKK3 expression may be altered and correlated with aberrant NFkappaB activity. We show that stable cell lines overexpressing MEKK3 not only had elevated levels of NFkappaB binding activity but also were more responsive to cytokine stimulation. These stable cells showed 2-4-fold higher basal expression of Bcl-2 and xIAP than the parental cells. Consistent with this increased expression of cell survival genes, MEKK3 stable cells showed reduced activation of caspases 3 and 8 and poly(ADP-ribose) polymerase cleavage and dramatically increased resistance to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand, doxorubicin, daunorubicin, camptothecin, and paclitaxel. Intriguingly, analysis of human breast and ovarian cancers showed that a significant fraction of these samples have elevated MEKK3 protein levels with corresponding increases in NFkappaB binding activities. Thus, our results established that elevated expression of MEKK3 appears to be a frequent occurrence in breast and ovarian cancers and that overexpression of MEKK3 in cells leads to increased NFkappaB activity and increased expression of cell survival factors and ultimately contributes to their resistance to apoptosis. As such, MEKK3 may serve as a therapeutic target to control cancer cell resistance to cytokine- or drug-induced apoptosis.

Apoptosis↗
PubMed2003

Lipoic acid protects efficiently only against a specific form of peroxynitrite-induced damage.

The ability of the sulfur-containing compounds glutathione (GSH), glutathione disulphide (GSSG), S-methylglutathione (GSMe), lipoic acid (LA), and dihydrolipoic acid (DHLA) to protect against hypochlorous acid (HOCl)-mediated damage and peroxynitrite (ONOOH)-induced damage has been compared. Protective activity was assessed in competition assays by monitoring several detectors, i.e. dihydrorhodamine-123 (DHR-123) oxidation, alpha(1)-antiproteinase (alpha(1)-AP) inactivation, and glutathione S-transferase P1-1 (GST-P1-1) inactivation. In addition, nitration of tyrosine was measured to assess protection of the sulfur-containing compounds against ONOOH. For protection against HOCl, the efficacy of the antioxidant was controlled by the ratio of the reaction rates of the antioxidant and the detector molecule with the oxidant. The rank order of the activity of the antioxidants (GSH > DHLA approximately LA approximately GSMe > GSSG) appeared to be independent of the detector used. However, the rank order of the antioxidants against ONOOH-induced damage is strongly dependent on the detector. LA was 40 times less active than GSH in the inhibition of ONOOH-induced DHR-123 oxidation, whereas LA was 20 times more active than GSH in preventing the inhibition of GST-P1-1 by ONOOH. This points to different molecular mechanisms of ONOOH damage to DHR-123 compared with ONOOH damage to GST-P1-1. LA is a poor antioxidant in protecting against the form of ONOOH damage involved in DHR-123 oxidation. In the form of ONOOH toxicity involved in GST-P1-1 inhibition, LA is the most potent sulfur-containing antioxidant in our series. It is proposed that an intermediate product in which both sulfur atoms of LA have reacted is involved in the reaction of ONOOH with LA. The high potency of LA to protect GST-P1-1 against ONOOH might be of therapeutic interest.

Antioxidants↗
PubMed2004

Genes affecting the cell cycle, growth, maintenance, and drug sensitivity are preferentially regulated by anti-HER2 antibody through phosphatidylinositol 3-kinase-AKT signaling.

The molecular mechanisms by which the anti-HER2 antibodies trastuzumab and its murine equivalent 4D5 inhibit tumor growth and potentiate chemotherapy are not fully understood. Inhibition of signaling through the phosphatidylinositol 3-kinase (PI3K)-AKT pathway may be particularly important. Treatment of breast cancer cells that overexpress HER2 with trastuzumab inhibited HER2-HER3 association, decreased PDK1 activity, reduced Thr-308 and Ser-473 phosphorylation of AKT, and reduced AKT enzymatic activity. To place the role of PI3K-AKT in perspective, gene expression was studied by using Affymetrix microarrays and real time reverse transcription-PCR. Sixteen genes were consistently down-regulated 2.0-4.9-fold in two antibody-treated breast cancer cell lines. Fourteen of the 16 genes were involved in three major functional areas as follows: 7 in cell cycle regulation, particularly of the G(2)-M; 5 in DNA repair/replication; and 2 in modifying chromatin structure. Of the 16 antibody-regulated genes, 64% had roles in cell growth/maintenance and 52% contributed to the cell cycle. Direct inhibition of PI3K with an inhibitor markedly reduced expression of 14 genes that were also affected by the antibody. Constitutive activation of AKT1 blocked the effect of the anti-HER2 antibody on cell cycle arrest and on eight differentially expressed genes. The antibody enhanced docetaxel-induced growth inhibition but did not increase the fraction of apoptotic cells induced with docetaxel alone. In contrast, the antibody plus docetaxel markedly down-regulated two genes, HEC and DEEPEST, required for passage through G(2)-M. Thus, anti-HER2 antibody preferentially affects genes contributing to cell cycle progression and cell growth/maintenance, in part through the PI3K-AKT signaling. Transcriptional regulation by anti-HER2 antibody through PI3K-AKT pathway may potentiate the growth inhibitory activity of docetaxel by affecting cell cycle progression.

Antibodies, Monoclonal↗
PubMed2001

Transcription factor NF-kappaB as a potential biomarker for oxidative stress.

There is increasing interest in the involvement of transcription factors, such as of the transcription factor NF-kappaB (nuclear factor-kappaB), in the pathogenesis of various diseases. NF-kappaB is involved in the control of the transcription of a variety of cellular genes that regulate the inflammatory response by the production of cytokines, chemokines, cell adhesion molecules and acute phase proteins. The involvement of NF-kappaB is especially of interest as it is activated by oxidative stress and its activation can be modulated by antioxidant compounds. The activation of NF-kappaB can be determined by the electromobility shift assay (EMSA) with a NF-kappaB binding-site-specific probe. EMSA can also be used on human mononuclear cells isolated from peripheral blood, which could make the assay applicable for clinical trials. The critical steps of the EMSA are discussed, addressing some pitfalls of the assay. The procedure that can be used to express NF-kappaB activity in human subjects is evaluated. This offers the possibility to use NF-kappaB as a functional biomarker of oxidative stress as illustrated by several examples of in vitro and in vivo studies.

Biomarkers↗
PubMed2001

Antioxidant supplementation and exercise-induced oxidative stress in the 60-year-old as measured by antipyrine hydroxylates.

The effects of 12 weeks of antioxidant supplementation on exercise-induced oxidative stress were investigated in older adults (60 (SE 1) years; BMI 26 (SE 1) kg/m(2)). Subjects were randomly divided in two groups: supplementation (n 11) with 100 mg dl-alpha-tocopheryl acetate, 200 mg ascorbic acid, and 2 mg beta-carotene, and placebo (n 9). Before and after the 12 week supplementation period, subjects cycled for 45 min at submaximal intensity (50 % maximal workload capacity). Antipyrine was used as marker for oxidative stress. Antipyrine reacts quickly with hydroxyl radicals to form para- and ortho-hydroxyantipyrine. The latter metabolite is not formed in man through the mono-oxygenase pathway of cytochrome P450. Daily supplementation significantly increased plasma concentrations of alpha-tocopherol and beta-carotene in the supplemented group (Delta 14.4 (SE 3.2) and 0.4 (se 0.1) micromol/l; P<0.001 and P<0.01). No significant differences, within and between groups, were observed in the exercise-induced increase in the ratios para- and ortho-hydroxyantipyrine to antipyrine. In addition, supplementation did not affect the exercise-induced increase in thiobarbituric acid reactive substances in plasma. In conclusion, in 60-year-old subjects antioxidant supplementation had no effect on the exercise-induced increase in oxidative stress as measured by free radical products of antipyrine.

Antioxidants↗
PubMed1998

Physiologic and pathologic drug resistance in ovarian carcinoma--a hypothesis based on a clonal progression model.

Conventional models for successful chemotherapy suggest that early-stage ovarian cancer should be more responsive to cytotoxic drugs than advanced disease, that multiple drugs will prove more efficacious than single agents and that more intensive chemotherapy will prove superior to conventional doses. The purpose of numerous clinical studies has been to test these predictions and the results often fall short of the expectations. In trials to date, adjuvant chemotherapy for high-risk, early-stage ovarian cancer has provided only a modest, equivocal increase in disease-free survival. Combination chemotherapy produces higher response rates but this has not consistently resulted in prolonged survival. Dose intensification with high-dose chemotherapy increases rate of response further, but most responses are of short duration. The objective of this review is to integrate clinical and molecular biological observations into a novel model of drug resistance. We hypothesize that drug sensitivity is an acquired characteristic of neoplastic cells, and that there are two broad cellular forms of resistance to cytotoxic drugs. 'Physiological drug resistance' is a cellular state when drug sensitivity of cancer cells is similar to that of the corresponding normal tissue. This form of drug resistance can precede the acquisition of drug sensitivity and may be predominant in the early stages of neoplastic progression. A distinct, 'pathological drug resistance' can reappear later during tumor progression or during chemotherapy as a result of increased detoxification, upregulation of repair pathways or defective apoptosis. Tumors are formed of heterogeneous cell populations and in terms of drug sensitivity three distinct cell types may be present: drug-sensitive, physiologically drug-resistant and pathologically drug-resistant. Clinical response to chemotherapy is determined by the relative contribution of these different cell populations to the total cellular mass. Depending on the predominant type of surviving population, distinct patterns of clinical failure may develop that require different treatment strategies for optimal management. For chemosensitive cells that survived insufficient chemotherapy, consolidation with further, perhaps, high-dose chemotherapy is a rational option. For pathologically drug-resistant cells, pharmacological manipulation of drug resistance, and signaling pathways in combination with chemotherapy could be exploited. For physiologically drug-resistant cells, non-chemotherapy-based, 'chemopreventive' strategies to arrest tumor progression may prove beneficial.

Apoptosis↗
PubMed1998

Obstetrical and neonatal outcome in pregnant patients with rheumatic disease.

Possible associations between inflammatory rheumatic and connective tissue disease and adverse pregnancy outcome were assessed by using the Medical Birth Registry of Norway during the years 1967-95. All women with rheumatic disease were compared to women without such disease. Data on pregnancy outcome and deliveries were analyzed after adjustment for possible confounding factors. Women with rheumatic disease had significantly higher rates of preeclampsia, premature delivery and cesarean section as well a significantly increased relative risk of SGA children in all diagnostic groups in 1967-95. These findings emphasize the importance of close monitoring of pregnancy and delivery not only in patients with connective tissue disease, but also in patients with other inflammatory rheumatic disease.

Adult↗
PubMed1999

Perinatal outcome in pregnancies of women with connective tissue disease and inflammatory rheumatic disease in Norway.

Perinatal outcome in infants of women with rheumatic disease notified between 1967 95 to the Medical Birth Registry of Norway was compared to women without such disease. Logistic regression provided odds ratios for associations between rheumatic disease and perinatal outcome for 3 time periods: 1967-76, 1977-86, and 1987-95. Women with rheumatic disease had significantly higher rates of preterm birth than references and this was only partly correlated to the increased occurrence of preeclampsia. The risk of small for gestational age (SGA) infants was significantly higher both in women with connective tissue disease (CTD) and inflammatory arthritides. The proportion of infants with Apgar score < = 6 after 1 minute and 5 minutes was significantly increased in the CTD group indicating moderate to severe fetal asfyxia. The rate of perinatal mortality was high in the CTD group and postperinatal mortality was increased in infants born to mothers with rheumatic disease. Thus, rheumatic disease not only comprises pregnancy outcome, but increases the risk of adverse perinatal outcome.

Apgar Score↗
PubMed1998

Secular trends in breastfeeding and parental smoking.

To explore the association between smoking and breastfeeding, we obtained data from a retrospective questionnaire-based national survey comprising a random sample (n = 34799) of all mothers giving birth in Norway 1970-91. Variables studied were postpartum smoking habits for both parents, duration of breastfeeding, infant's year of birth and parental age. The response rate was 70% (n = 24438). During the study period, the maternal postpartum smoking prevalence decreased from 38% to 26%. The proportion breastfeeding at 6 months increased from 15% to 44% among smokers, and from 30% to 72% among non-smokers. In spite of a considerable increase in breastfeeding both among smokers and non-smokers, the proportion of breastfeeding, non-smoking women at 6 months was twice that of smoking women during the whole period. Furthermore, the duration of breastfeeding was shorter among young mothers and when the fathers were smoking. There was epidemiological evidence that the effect on breastfeeding of smoking might represent both biological and social mechanisms.

Adult↗
PubMed1997

Improving physician-patient communication in cancer care: outcome of a workshop for oncologists.

BACKGROUND: Physicians caring for cancer patients receive little formal training in difficult communications such as breaking bad news, discussing life support, and addressing patients' emotional concerns. METHODS: The authors conducted a three-day workshop in communication skills for nine oncology attendings and three fellows. Topics for the workshop were selected by participants by a pre-workshop questionnaire. Small groups of four to five participants interviewed simulated patients who role-played scripts based on the selected topics. Sessions on self-awareness and one on planning for continuing the work of the group after the workshop were included. RESULTS: Responses to pretest and posttest questionnaires showed that the workshop increased the participants' confidence in a number of communication areas and also in managing physician burnout. Process issues such as patient death and expectations for cure were also discussed. CONCLUSION: Interactive workshops offer a promising way of teaching communication skills and aspects of the physician-patient relationship to oncologists. Conclusions regarding outcome, however, are preliminary and tentative, and long-term results are uncertain.

Cancer Care Facilities↗
PubMed1999

The effect of 2'-2' difluorodeoxycytidine (dFdC, gemcitabine) on radiation-induced cell lethality in two human head and neck squamous carcinoma cell lines differing in intrinsic radiosensitivity.

PURPOSE: The present study investigated in vitro radio-enhancement by gemcitabine (dFdC) in two head and neck squamous cell carcinomas with different intrinsic cellular radiosensitivity. MATERIALS AND METHODS: Radiosensitive (SCC61, SF2=0.16) and radioresistant (SQD9, SF2=0.49) human head and neck squamous cell carcinomas were used. Confluent cells were incubated with dFdC and irradiated in drug-free medium with a single dose of 250 kV X-rays (0-12Gy). Cell survival curves were corrected for the toxicity of the drug alone. RESULTS: In both cell lines, radio-enhancement was observed with 5 microM dFdC incubated for 3 h prior to irradiation. Dose modification factors (DMF) at a surviving fraction level of 0.5 reached 1.3 (95% CI 1.1-1.6) and 1.5 (95% CI 1.4-1.5) for SQD9 and SCC61 cells, respectively. Radio-enhancement was associated with a modest increase in the alpha term of the linear-quadratic model. In SQD9 cells, radio-enhancement increased with dFdC incubation time. At 24h, DMF reached a value of 1.5 (95% CI 0.9-3.2). In SCC61 cells at 24h, DMF reached a value of 1.1 (95% CI 0.9-1.2). In both cell lines, radio-enhancement increased with dFdC concentration up to 5-10 microM from which values it levelled off up to 100 microM. CONCLUSIONS: The data indicated that dFdC induced a modest radio-enhancement in both cell lines. For a short incubation time, dFdC did not radio-enhance preferentially the more radio-resistant cells, whereas the opposite was observed for a longer time. In both cell lines, radio-enhancement was saturated above a dFdC concentration of 5-10 microM.

Carcinoma, Squamous Cell↗
PubMed2002

CNOP for diffuse aggressive non-Hodgkin's lymphoma: the Nebraska lymphoma study group experience.

The purpose of this study was to evaluate the CNOP regimen (cyclophosphamide, mitoxantrone, vincristine, and prednisone) throughout a community based oncology network with a large number of elderly non-Hodgkin's lymphoma (NHL) patients. Three hundred and seventy-three previously untreated patients with diffuse aggressive NHL received the CNOP regimen administered through a community oncology network, the Nebraska Lymphoma Study Group (NLSG). The complete response rate was 60% with an overall response rate of 73%. The estimated 4-year event-free survival for patients <60years was 44%, compared to 38% for those >age 60 (p = 0.18). However, the 4-year estimated overall survival for patients <60 years was 62% compared to 44% for those >60 years (p < 0.001). Prognostic factors predictive for a poor event-free survival were male gender, stage III/IV disease, Karnofsky score <80, and elevated lactic dehydrogenase (LDH). The lymphoma specific cumulative death rate was 29% for patients <60 years compared with 33% for patients >60 years (p = 0.07). After failing CNOP the 4-year overall survival (OS) was 19%. The estimated 4-year OS for patients who failed CNOP and went on to receive high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplant (ASCT) was 64% for patients < age 60 and 48% for those >60 years (p = 0.23). In conclusion, CNOP chemotherapy administered to patients with diffuse aggressive NHL in a community oncology network produces similar result to that reported for other anthracycline based regimens reported in the literature. Patients >age 60 had a higher rate of failure due to causes other than lymphoma which accounted for a worse survival long-term. However, patients of all ages who failed CNOP and who were able to receive HDC and ASCT demonstrated long-term disease survival after the transplant.

Adolescent↗
PubMed2001

Exercise training and oxidative stress in the elderly as measured by antipyrine hydroxylation products.

Effects of 12 wk exercise training on oxidative stress were examined in elderly humans. We measured oxidative stress during a 45 min cycling test by using antipyrine hydroxylation products. Antipyrine breakdown is independent of blood flow to the liver, which is important during exercise. Furthermore, antipyrine reacts quickly with hydroxyl radicals to form para- and ortho-hydroxyantipyrine. Ortho-hydroxyantipyrine is not formed in man through the mono-oxygenase pathway of cytochrome P450. Twenty subjects (9 women; 60 +/- 3 y) participated in the training program. Thirteen subjects (5 women; 64 +/- 7 y) served as inactive controls. Subjects trained, twice a week for 1 h, at a fitness center. After 12 wk, maximal oxygen uptake (p < .005) and workload capacity (p < .001) were only significantly elevated in the training group. After 12 wk, both groups observed no change in the ratios of antipyrine hydroxylates, para- and ortho-hydroxyantipyrine, to native antipyrine. Furthermore, no differences were observed within or between groups in the exercise-induced increase in the plasma level of thiobarbituric acid reactive species. In conclusion, 12-wk training had no effect on exercise-induced oxidative stress in elderly humans as measured by free radical reaction products of antipyrine. Despite the fact that training in elderly humans improves functional capacity, it appears not to compromise antioxidant defense mechanisms.

Aging↗
PubMed2002

Protection of flavonoids against lipid peroxidation: the structure activity relationship revisited.

The inhibition of the lipid peroxidation, induced by iron and ascorbate in rat liver microsomes, by phenols and flavones was studied. The activity of phenol was enhanced by electron donating substituents, denoted by the Hammett sigma (sigma). The concentration of the substituted phenols giving 50% inhibition (IC50) of lipid peroxidation gave a good correlation with the sigma of the substituent (ln(1/IC50) = -8.92sigma + 5.80 (R = 0.94, p < 0.05)). In flavones two pharmacophores for the protection against lipid peroxidation were pinpointed: (i) a catechol moiety as ring B and (ii) an OH-group at the 3 position with electron donating groups at the 5 and/or 7 position in the AC-ring. An example of a flavone with the latter pharmacophore is galangin (3,5,7-trihydroxyflavone) where the reactivity of the 3-OH-group is enhanced by the electron donating effect of the 5- and 7-OH-groups. This is comparable to the effect of electron donating substituents on the activity of phenol. The prooxidant activity of flavones has been related to a low half peak oxidation potential (Ep/2). All flavones with a catechol as ring B have very low Ep/2, suggesting that they display a prominent prooxidant activity. In contrast, the Ep/2 varies within the group of flavones with a 3-OH, e.g. TUM 8436 (5,7,3',4'-tetra-O-methyl-quercetin) has a relatively high Ep/2 and is an excellent protector against lipid peroxidation. Apparently amongst the flavones with the pharmacophore in the AC-ring there are good antioxidants that are expected to display no or limited prooxidant properties.

Animals↗
PubMed2006

ATP inhibits hydroxyl radical formation and the inflammatory response of stimulated whole blood even under circumstances of severe oxidative stress.

We recently reported that Adenosine-5'-triphosphate (ATP) is able to inhibit the inflammatory reaction in stimulated whole blood. Many diseases, in which inflammatory reactions are involved, are associated with oxidative stress. In the present study, we therefore, investigated the effect of ATP on cytokine release in stimulated whole blood under conditions of oxidative stress, as simulated by pre-incubation of blood with hydrogen peroxide (H(2)O(2)). In the presence of H(2)O(2), ATP at concentrations of 100 and 300 microM inhibited Tumour Necrosis factor-alpha (TNF-alpha) release and stimulated IL-10 release in LPS-PHA stimulated whole blood. Moreover, electron spin resonance (ESR) measurements showed that ATP and its breakdown product Adenosine-5'-diphosphate (ADP) attenuated spin trap-hydroxyl radical adduct formation in the Fenton reaction. Our results demonstrate that even in circumstances of severe oxidative stress, ATP has marked anti-inflammatory properties in stimulated whole blood. Moreover, the inhibition of the hydroxyl radical ESR signal indicates a direct attenuation of oxidative stress by ATP.

Adenosine Triphosphate↗
PubMed2006

Free radicals in exhaled breath condensate in cystic fibrosis and healthy subjects.

Many markers of airway inflammation and oxidative stress can be measured non-invasively in exhaled breath condensate (EBC). However, no attempt has been made to directly detect free radicals using electron paramagnetic resonance (EPR) spectroscopy. Condensate was collected in 14 children with cystic fibrosis (CF) and seven healthy subjects. Free radicals were trapped by 5,5-dimethyl-1-pyrroline-N-oxide. EPR spectra were recorded using a Bruker EMX spectrometer. Secondly, to study the source of oxygen centered radical formation, catalase or hydrogen peroxide was added to the condensate. Radicals were detected in 18 out of 21 condensate samples. Analysis of spectra indicated that both oxygen and carbon centered radicals were trapped. Within-subject reproducibility was good in all but one subject. Quantitatively, there was a trend towards higher maximal peak heights of both oxygen and carbon centered radicals in the children with CF. Catalase completely suppressed the signals in condensate. Addition of hydrogen peroxide resulted in increased radical signal intensity. Detection of free radicals in EBC of children with CF and healthy subjects is feasible using EPR spectroscopy.

Adolescent↗
PubMedDate not supplied

The effect of the trolox equivalent antioxidant capacity (TEAC) in plasma on the formation of 4-aminobiphenylhaemoglobin adducts in smokers.

Smokers are exposed to a number of carcinogenic compounds including aromatic amines such as 4-aminobiphenyl. Antioxidants are thought to be involved in the defence against the damaging effect of such carcinogens. Recently it has been shown that plasma antioxidant status in smokers is diminished compared with non-smokers. In this study we investigated in 40 smokers whether the trolox equivalent antioxidant capacity (TEAC) in plasma could be quantitatively related to exposure to cigarette smoke. The biomarkers 4-aminobiphenylhaemoglobin (4-ABP-Hb) adduct and cotinine were determined as indices of cigarette smoke exposure. A correlation between 4-ABP-Hb adduct levels and plasma cotinine levels was found for the whole population studied, who smoked 4-70 cigarettes per day (n = 40, r(2) = 0.12, p = 0.03). A significant inverse relationship was found between TEAC and 4-ABP-Hb levels (n = 40, r(2) = 0.17, p = 0.008). Multiple regression analysis showed a strong relationship between 4-ABP-Hb levels and plasma TEAC and cotinine levels (n = 40, r(2) =0.29, p = 0.002). These findings provide strong evidence that the 4- ABP-Hb adduct represents a valuable biomarker of (internal) exposure to tobacco smoke, and also that the formation of this marker is dependent on the plasma antioxidant status. The multiple regression analysis results show that the measure of effect (4-ABP-Hb adduct formation) is largely determined by dose (cotinine) and protection (TEAC).

Adult↗
PubMed2002

Tocotrienols inhibit human glutathione S-transferase P1-1.

Tocopherols and tocotrienols are food ingredients that are believed to have a positive effect on health. The most studied property of both groups of compounds is their antioxidant action. Previously, we found that tocopherols and diverse tocopherol derivatives can inhibit the activity of human glutathione S-transferase P1-1 (GST P1-1). In this study we found that GST P1-1 is also inhibited, in a concentration-dependent manner, by alpha- and gamma-tocotrienol. The concentration giving 50% inhibition of GST P1-1 is 1.8 +/- 0.1 microM for alpha-tocotrienol and 0.7 +/- 0.1 microM for gamma-tocotrienol. This inhibition of GST P1-1 is noncompetitive with respect to both substrates CDNB and GSH. We also examined the 3D structure of GST P1-1 for a possible tocopherol/tocotrienol binding site. The enzyme contains a very hydrophobic pit-like structure where the phytyl tail of tocopherols and tocotrienols could fit in. Binding of tocopherol and tocotrienol to this hydrophobic region might lead to bending of the 3D structure. In this way tocopherols and tocotrienols can inhibit the activity of the enzyme; this inhibition can have far-reaching implications for humans.

Antioxidants↗