The Experts below are selected from a list of 264 Experts worldwide ranked by ideXlab platform
Paul Talalay - One of the best experts on this subject based on the ideXlab platform.
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a major Inducer of anticarcinogenic protective Enzymes from broccoli isolation and elucidation of structure chemoprotection Enzyme induction isothiocyanates sulforaphane quinone reductase
2016Co-Authors: Yuesheng Zhang, Paul Talalay, Gary H PosnertAbstract:Consumption of vegetables, especially cruci- fers, reduces the risk of developing cancer. Although the mechanisms of this protection are unclear, feeding of vegeta- bles induces Enzymes of xenobiotic metabolism and thereby accelerates the metabolic disposal of xenobiotics. Induction of phase II detoxication Enzymes, such as quinone reductase (NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2) and glutathione S-transferases (EC 2.5.1.18) in rodent tissues affords protection against carcinogens and other toxic electro- philes. To determine whether Enzyme induction is responsible for the protective properties of vegetables in humans requires isolation of Enzyme Inducers from these sources. By monitoring quinone reductase induction in cultured murine hepatoma cells as the biological assay, we have isolated and identified (-)-1- isothiocyanato-(4R)-(methylsulfinyl)butane (CH3-SO- (CH2)4-NCS, sulforaphane) as a major and very potent phase II Enzyme Inducer in SAGA broccoli (Brassica oleracea italica). Sulforaphane is a monofunctional Inducer, like other anticar- cinogenic isothiocyanates, and induces phase II Enzymes selec-
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powerful and prolonged protection of human retinal pigment epithelial cells keratinocytes and mouse leukemia cells against oxidative damage the indirect antioxidant effects of sulforaphane
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Xiangqun Gao, Albena T Dinkovakostova, Paul TalalayAbstract:Mammalian cells are equipped with elaborate systems for protection against the toxicity of reactive oxygen and nitrogen species and electrophiles that are constant dangers to the integrity of their DNA. Phase 2 Enzymes (e.g., glutathione transferases, NAD(P)H:quinone reductase) and glutathione synthesis are widely recognized as playing major protective roles against electrophilic carcinogens, but their antioxidant functions have attracted far less attention. The cytotoxicities of four oxidative stressors (menadione, tert-butyl hydroperoxide, 4-hydroxynonenal, and peroxynitrite) for human adult retinal pigment epithelial cells (ARPE-19) were quantified by measuring the concentration dependence of cell death and were expressed as the median effect dose (D(m)) for each oxidant. After treatment of ARPE-19 cells for 24 h with 0-5 microM concentrations of sulforaphane (the powerful Phase 2 Enzyme Inducer isolated from broccoli), the toxicities of the oxidants were markedly reduced as shown by 1.5- to 3-fold increases in D(m) values. The magnitude of protection was a function of the nature of the oxidants and the concentrations of both the oxidants and sulforaphane. Protection was prolonged and persisted for several days after removal of sulforaphane before returning to control levels. The sulforaphane-dependent increases in specific activities of cytosolic quinone reductase and the glutathione levels were highly significantly correlated with the degree of protection as measured by D(m) values. Antioxidant protection was also demonstrated for human HaCaT keratinocytes and L1210 murine leukemia cells. It is therefore highly likely that the multifaceted and prolonged antioxidant protection provided by sulforaphane is a general phenomenon that is mediated through induction of the Phase 2 Enzyme response.
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mechanism of differential potencies of isothiocyanates as Inducers of anticarcinogenic phase 2 Enzymes
Cancer Research, 1998Co-Authors: Yuesheng Zhang, Paul TalalayAbstract:Abstract Isothiocyanates occur in many edible plants and are consumed in substantial quantities by humans. A number of isothiocyanates block chemical carcinogenesis in a variety of animal models by inhibiting Phase 1 Enzymes involved in carcinogen activation and by inducing Phase 2 Enzymes that accelerate the inactivation of carcinogens. There are large but unexplained potency differences among individual isothiocyanates. When murine hepatoma (Hepa 1c1c7) and several other cell lines were exposed to low concentrations (1–5 µm) of certain isothiocyanates, the intracellular isothiocyanate/dithiocarbamate concentrations (measured by cyclocondensation with 1,2-benzenedithiol) rose rapidly (30 min at 37°C) to very high levels ( e.g. , 800–900 µm). The intracellular accumulation of isothiocyanates/dithiocarbamates was temperature, structure, and glutathione dependent and could not be saturated under experimentally achievable conditions. When murine hepatoma cells were exposed to nine isothiocyanates (5 µm for 24 h at 37°C) that differed considerably in structure and Phase 2 Enzyme Inducer potencies, the intracellular concentrations (area under curve) correlated closely and linearly with their potencies as Inducers of the Phase 2 Enzymes: NAD(P)H:quinone reductase and glutathione S -transferases. Isothiocyanates that did not accumulate to high levels were not Inducers. These observations suggest strongly that induction of Phase 2 Enzymes depends on intracellular levels of isothiocyanates/dithiocarbamates. Depletion of glutathione by treatment of Hepa cells with buthionine sulfoximine increased the Inducer potencies of several isothiocyanates but could not be directly related to changes in intracellular isothiocyanate/dithiocarbamate concentrations, suggesting that glutathione may play several roles in the induction process.
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broccoli sprouts an exceptionally rich source of Inducers of Enzymes that protect against chemical carcinogens
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Jed W Fahey, Yuesheng Zhang, Paul TalalayAbstract:Abstract Induction of phase 2 detoxication Enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen. Since consumption of large quantities of fruit and vegetables is associated with a striking reduction in the risk of developing a variety of malignancies, it is of interest that a number of edible plants contain substantial quantities of compounds that regulate mammalian Enzymes of xenobiotic metabolism. Thus, edible plants belonging to the family Cruciferae and genus Brassica (e.g., broccoli and cauliflower) contain substantial quantities of isothiocyanates (mostly in the form of their glucosinolate precursors) some of which (e.g., sulforaphane or 4-methylsulfinylbutyl isothiocyanate) are very potent Inducers of phase 2 Enzymes. Unexpectedly, 3-day-old sprouts of cultivars of certain crucifers including broccoli and cauliflower contain 10–100 times higher levels of glucoraphanin (the glucosinolate of sulforaphane) than do the corresponding mature plants. Glucosinolates and isothiocyanates can be efficiently extracted from plants, without hydrolysis of glucosinolates by myrosinase, by homogenization in a mixture of equal volumes of dimethyl sulfoxide, dimethylformamide, and acetonitrile at −50°C. Extracts of 3-day-old broccoli sprouts (containing either glucoraphanin or sulforaphane as the principal Enzyme Inducer) were highly effective in reducing the incidence, multiplicity, and rate of development of mammary tumors in dimethylbenz(a)anthracene-treated rats. Notably, sprouts of many broccoli cultivars contain negligible quantities of indole glucosinolates, which predominate in the mature vegetable and may give rise to degradation products (e.g., indole-3-carbinol) that can enhance tumorigenesis. Hence, small quantities of crucifer sprouts may protect against the risk of cancer as effectively as much larger quantities of mature vegetables of the same variety.
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chemoprotection against cancer by phase 2 Enzyme induction
Toxicology Letters, 1995Co-Authors: Paul Talalay, Jed W Fahey, David W Holtzclaw, Tory Prestera, Yuesheng ZhangAbstract:Abstract Mammalian cells have evolved elaborate mechanisms for protection against the toxic and neoplastic effects of electrophilic metabolites of carcinogens and reactive oxygen species. Phase 2 Enzymes (e.g. glutathione transferase, NAD(P)H:quinone reductase, UDP-glucuronosyltransferases) and high intracellular levels of glutathione play a prominent role in providing such protection. Phase 2 Enzymes are transcriptionally induced by low concentrations of a wide variety of chemical agents and such induction blocks chemical carcinogenesis. The Inducers belong to many chemical classes including phenolic antioxidants, Michael reaction acceptors, isothiocyanates, 1,2-dithiole-3-thiones, trivalent arsenicals, HgCl2 and organomercurials, hydroperoxides, and vicinal dimercaptans. Induction by all classes of Inducers involves the antioxidant/electrophile response element (ARE/EpRE). Inducers are widely, but unequally, distributed among edible plants. Search for such Inducer activity in broccoli led to the isolation of sulforaphane, an isothiocyanate that is a very potent Phase 2 Enzyme Inducer and blocks mammary tumor formation in rats.
Thomas W. Kensler - One of the best experts on this subject based on the ideXlab platform.
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induction of 26s proteasome subunit psmb5 by the bifunctional Inducer 3 methylcholanthrene through the nrf2 are but not the ahr arnt xre pathway
Biochemical and Biophysical Research Communications, 2006Co-Authors: Mi Kyoung Kwak, Thomas W. KenslerAbstract:The 26S proteasome is responsible for degradation of abnormal intracellular proteins, including oxidatively damaged proteins and may play a role as a component of a cellular antioxidative system. However, little is known about regulation of proteasome expression. In the present study, regulation of proteasome expression by the bifunctional Enzyme Inducer and a specific signaling pathway for this regulation were investigated in murine neuroblastoma cells. Expression of catalytic core subunits including PSMB5 and peptidase activities of the proteasome were elevated following incubation with 3-methylcholanthrene (3-MC). Studies using reporter genes containing the murine Psmb5 promoter showed that transcriptional activity of this gene was enhanced by 3-MC. Overexpression of AhR/Arnt did not affect activation of the Pmsb5 promoter by 3-MC and deletion of the xenobiotic response elements (XREs) from this promoter exerted modest effects on inducibility in response to 3-MC. However, mutation of the proximal AREs of the Psmb5 promoter largely abrogated its inducibility by 3-MC. In addition, this promoter showed a blunted response toward 3-MC in the absence of nrf2; 3-MC incubation increased nuclear levels of Nrf2 only in wild-type cells. Collectively, these results indicate that expression of proteasome subunit PSMB5 is modulated by bifunctional Enzyme Inducers in a manner independent of the AhR/Arnt-XRE pathway but dependent upon the Nrf2-ARE pathway.
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Phase 2 Enzyme Induction by the Major Metabolite of Oltipraz
Chemical research in toxicology, 2003Co-Authors: Jacobus P. Petzer, Mi Kyoung Kwak, Thomas W. Kensler, Mettachit Navamal, Jesse K. Johnson, James C. FishbeinAbstract:Treatment for 48 h of murine Hepa 1c1c7 cells in culture with the cancer chemopreventive oltipraz (1) followed by addition of CD(3)I and immediate cell lysis yields, by LC/MS analysis, three isotopomers of the methylated pyrrolopyrazine (2), a known human metabolite of oltipraz. The major isotopomer (58%) is the one containing two CD(3)- groups attached to the pendant sulfur atoms of the pyrrolopyrazine ring, the others containing one CD(3)- and one CH(3)- group or two CH(3)- groups. It is concluded from this that the unmethylated pyrrolopyrazine (4) is the major metabolite of oltipraz. Prodrugs 5 and 6, which have been shown to rapidly generate 4 in the presence of GSH at physiological pH, induce the phase 2 Enzyme NQO1 in Hepa 1c1c7 cells with potencies on par with oltipraz itself: CD(NQO1) = 14.4 +/- 1.3, 20.1 +/- 4.6, and 23.6 +/- 1.6 microM for oltipraz, 5, and 6, respectively. Pretreatment of oltipraz, 5, and 6 in cell culture media with 1 mM GSH, which is shown to immediately convert 5 and 6 to 4, followed by incubation with Hepa 1c1c7 cells shows similar potencies for oltipraz and the (decomposed) produrgs, with CD(NQO1) = 18.0 +/- 4.4 microM for 5, 17.8 +/- 0.2 microM for 6, and 13.5 +/- 1.4 microM for oltipraz. Treatment with compound 6 of murine hepatoma cells containing a luciferase gene under the control of the antioxidant response element (ARE) from the mouse heme oxygenase (ho-1) gene elicits induction of luciferase activity, CD = 35.8 +/- 2.8 microM, somewhat greater than the potency than oltipraz itself. Western blots of nuclear proteins isolated from Hepa 1c1c7 cells and probed with anti-Nrf2 indicate that as compared to vehicle DMSO, compound 6 stimulates nuclear translocation of Nrf2 from the cytosol. From this study, it is concluded that the major metabolite of the cancer chemopreventive oltipraz is a phase 2 Enzyme Inducer of comparable potency that activates the ARE and initiates nuclear translocation of transcription factor Nrf 2.
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enhanced expression of the transcription factor nrf2 by cancer chemopreventive agents role of antioxidant response element like sequences in the nrf2 promoter
Molecular and Cellular Biology, 2002Co-Authors: Mi Kyoung Kwak, Ken Itoh, Masayuki Yamamoto, Thomas W. KenslerAbstract:Induction of phase 2 Enzymes, which neutralize reactive electrophiles and act as indirect antioxidants, is an important mechanism for protection against carcinogenesis. The transcription factor Nrf2, which binds to the antioxidant response element (ARE) found in the upstream regulatory region of many phase 2 genes, is essential for the induction of these Enzymes. We have investigated the effect of the potent Enzyme Inducer and anticarcinogen 3H-1,2-dithiole-3-thione (D3T) on the fate of Nrf2 in murine keratinocytes. Both total and nuclear Nrf2 levels increased rapidly and persistently after treatment with D3T but could be blocked by cotreatment with cycloheximide. Nrf2 mRNA levels increased ∼2-fold 6 h after D3T treatment. To examine the transcriptional activation of Nrf2 by D3T, the proximal region (1 kb) of the nrf2 promoter was isolated. Deletion and mutagenesis analyses demonstrated that nrf2 promoter-luciferase reporter activity was enhanced by treatment with D3T and that ARE-like sequences were required for this activation. Gel shift assays with nuclear extracts from PE cells indicated that common factors bind to typical AREs and the ARE-like sequences of the nrf2 promoter. Direct binding of Nrf2 to its own promoter was demonstrated by chromatin immunoprecipitation assay. Overexpression of Nrf2 increased the activity of the nrf2 promoter-luciferase reporter, while expression of mutant Nrf2 protein repressed activity. Thus, Nrf2 appears to autoregulate its own expression through an ARE-like element located in the proximal region of its promoter, leading to persistent nuclear accumulation of Nrf2 and protracted induction of phase 2 genes in response to chemopreventive agents.
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enhanced expression of the transcription factor nrf2 by cancer chemopreventive agents role of antioxidant response element like sequences in the nrf2 promoter
Molecular and Cellular Biology, 2002Co-Authors: Mi Kyoung Kwak, Ken Itoh, Masayuki Yamamoto, Thomas W. KenslerAbstract:Induction of phase 2 Enzymes, which neutralize reactive electrophiles and act as indirect antioxidants, is an important mechanism for protection against carcinogenesis. The transcription factor Nrf2, which binds to the antioxidant response element (ARE) found in the upstream regulatory region of many phase 2 genes, is essential for the induction of these Enzymes. We have investigated the effect of the potent Enzyme Inducer and anticarcinogen 3H-1,2-dithiole-3-thione (D3T) on the fate of Nrf2 in murine keratinocytes. Both total and nuclear Nrf2 levels increased rapidly and persistently after treatment with D3T but could be blocked by cotreatment with cycloheximide. Nrf2 mRNA levels increased approximately 2-fold 6 h after D3T treatment. To examine the transcriptional activation of Nrf2 by D3T, the proximal region (1 kb) of the nrf2 promoter was isolated. Deletion and mutagenesis analyses demonstrated that nrf2 promoter-luciferase reporter activity was enhanced by treatment with D3T and that ARE-like sequences were required for this activation. Gel shift assays with nuclear extracts from PE cells indicated that common factors bind to typical AREs and the ARE-like sequences of the nrf2 promoter. Direct binding of Nrf2 to its own promoter was demonstrated by chromatin immunoprecipitation assay. Overexpression of Nrf2 increased the activity of the nrf2 promoter-luciferase reporter, while expression of mutant Nrf2 protein repressed activity. Thus, Nrf2 appears to autoregulate its own expression through an ARE-like element located in the proximal region of its promoter, leading to persistent nuclear accumulation of Nrf2 and protracted induction of phase 2 genes in response to chemopreventive agents.
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potent inhibition of aflatoxin induced hepatic tumorigenesis by the monofunctional Enzyme Inducer l 2 dithiole 3 thione
Carcinogenesis, 1992Co-Authors: Thomas W. Kensler, David L. Eaton, Thomas J. Curphey, John Davis Groopman, Bill D. RoebuckAbstract:: 1,2-Dithiole-3-thiones are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, radioprotective and chemoprotective properties. Several substituted 1,2-dithiole-3-thiones are used medicinally and one of these, oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], has been recently shown to be an inhibitor of aflatoxin B1 (AFB1) hepatocarcinogenesis in the rat. Structure-activity studies have been undertaken to probe the mechanisms by which dithiolethiones inhibit carcinogenesis. Such studies revealed that unsubstituted 1,2-dithiole-3-thione was more effective than oltipraz at inhibiting aflatoxin-DNA adduct formation in vivo and at inducing electrophile detoxication Enzymes in cell culture. In the present studies the effects of dietary administration of 1,2-dithiole-3-thione on the induction of xenobiotic metabolizing Enzymes and inhibition of aflatoxin-induced hepatic tumorigenesis were examined. Male F344 rats were fed graded doses of 1,2-dithiole-3-thione (0.001-0.03%) for 4 weeks. During the second and third weeks of 1,2-dithiole-3-thione feeding, rats were dosed by gavage with 250 micrograms of AFB1/kg five times a week. Rats were then restored to control AIN-76A diet 1 week after cessation of AFB1 dosing. At 4 months, focal areas of hepatocellular alteration were identified and quantified by staining sections of liver for gamma-glutamyltranspeptidase (GGT) activity and glutathione S-transferase P (GST-P) expression. Treatment with 1,2-dithiole-3-thione at the lowest dose (0.001%) reduced by greater than 80% the volume of liver occupied by GGT or GST-P foci; higher dietary concentrations provided greater than 98% reductions in the volume per cent of these markers for presumptive preneoplastic lesions. All dietary concentrations of 1,2-dithiole-3-thione resulted in significant elevations in hepatic GST activities. In accord with the protective effects against tumorigenesis, 4- to 6-fold increases in the specific activities of aflatoxin-glutathione conjugation were observed in cytosols prepared from livers of animals fed 1,2-dithiole-3-thione. By contrast, 1,2-dithiole-3-thione did not have any detectable inductive effects on hepatic microsomal cytochrome P450 levels or activities. Dietary administration of 1,2-dithiole-3-thione also elevated activities of GSTs and other phase II Enzymes in several extrahepatic organs. This broad pattern of induction of detoxication Enzymes by 1,2-dithiole-3-thione supports the potential widespread use of this compound as a protective agent against chemical carcinogenesis and other forms of electrophile toxicity.
Yuesheng Zhang - One of the best experts on this subject based on the ideXlab platform.
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a major Inducer of anticarcinogenic protective Enzymes from broccoli isolation and elucidation of structure chemoprotection Enzyme induction isothiocyanates sulforaphane quinone reductase
2016Co-Authors: Yuesheng Zhang, Paul Talalay, Gary H PosnertAbstract:Consumption of vegetables, especially cruci- fers, reduces the risk of developing cancer. Although the mechanisms of this protection are unclear, feeding of vegeta- bles induces Enzymes of xenobiotic metabolism and thereby accelerates the metabolic disposal of xenobiotics. Induction of phase II detoxication Enzymes, such as quinone reductase (NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2) and glutathione S-transferases (EC 2.5.1.18) in rodent tissues affords protection against carcinogens and other toxic electro- philes. To determine whether Enzyme induction is responsible for the protective properties of vegetables in humans requires isolation of Enzyme Inducers from these sources. By monitoring quinone reductase induction in cultured murine hepatoma cells as the biological assay, we have isolated and identified (-)-1- isothiocyanato-(4R)-(methylsulfinyl)butane (CH3-SO- (CH2)4-NCS, sulforaphane) as a major and very potent phase II Enzyme Inducer in SAGA broccoli (Brassica oleracea italica). Sulforaphane is a monofunctional Inducer, like other anticar- cinogenic isothiocyanates, and induces phase II Enzymes selec-
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phase ii Enzyme Inducer sulforaphane inhibits uvb induced ap 1 activation in human keratinocytes by a novel mechanism
Molecular Carcinogenesis, 2004Co-Authors: Ming Zhu, Yuesheng Zhang, Simon J Cooper, Ewa T Sikorski, John Rohwer, Timothy G BowdenAbstract:Ultraviolet (UV) light-induced activation of activator protein-1 (AP-1), resulting at least in part from oxidative stress, promotes skin carcinogenesis. It has not yet been determined whether elevating cellular phase II Enzymes and glutathione (GSH) levels inhibits the AP-1 activation. We have, therefore, examined the effects of two well-known Inducers of phase II Enzymes, sulforaphane (SF) and tert-butylhydroquinone (tBHQ), on UVB-induced AP-1 activation, with an AP-1-luciferase reporter plasmid that was stably transfected into human HaCaT keratinocytes (HCL14 cells). Exposure of HCL14 cells to SF or tBHQ led to the induction of quinone reductase-1 (QR-1), a marker of global cellular phase II Enzymes, as well as elevation of cellular GSH levels. Incubation of the cells with 1-10 microM SF or 11-45 microM tBHQ for 24 h resulted in up to 1.4-fold and 1.7-fold increase of QR-1 activity, respectively, and up to 1.5-fold and 1.6-fold increases in cellular GSH levels, respectively. AP-1 activation was dramatically enhanced by irradiating HCL14 cells with 250 J/m(2) of UVB. While the above SF treatment dose-dependently reduced the UVB-induced AP-1 activation in HCL14 cells, the tBHQ treatment did not, suggesting that elevating cellular phase II Enzymes and GSH levels may not lead to inhibition of UVB-induced AP-1 activation. Indeed, depleting cellular GSH by 80% did not affect UVB-induced AP-1 activation either. Subsequent electrophoretic mobility shift assays (EMSA) showed that SF added directly to the EMSAs inhibited AP-1 DNA binding activity, whereas tBHQ was ineffective. Taken together, our results indicated that elevating phase II Enzymes and GSH levels in human keratinocytes does not lead to significant inhibition of UVB-induced AP-1 activation. The inhibitory effect of SF on UVB-induced AP-1 activation appears to be at least partly due to the direct inhibition of AP-1 DNA binding activity. This direct effect of SF on AP-1 DNA binding is a novel mechanism for the action of a drug inhibitor of AP-1 activation.
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mechanism of differential potencies of isothiocyanates as Inducers of anticarcinogenic phase 2 Enzymes
Cancer Research, 1998Co-Authors: Yuesheng Zhang, Paul TalalayAbstract:Abstract Isothiocyanates occur in many edible plants and are consumed in substantial quantities by humans. A number of isothiocyanates block chemical carcinogenesis in a variety of animal models by inhibiting Phase 1 Enzymes involved in carcinogen activation and by inducing Phase 2 Enzymes that accelerate the inactivation of carcinogens. There are large but unexplained potency differences among individual isothiocyanates. When murine hepatoma (Hepa 1c1c7) and several other cell lines were exposed to low concentrations (1–5 µm) of certain isothiocyanates, the intracellular isothiocyanate/dithiocarbamate concentrations (measured by cyclocondensation with 1,2-benzenedithiol) rose rapidly (30 min at 37°C) to very high levels ( e.g. , 800–900 µm). The intracellular accumulation of isothiocyanates/dithiocarbamates was temperature, structure, and glutathione dependent and could not be saturated under experimentally achievable conditions. When murine hepatoma cells were exposed to nine isothiocyanates (5 µm for 24 h at 37°C) that differed considerably in structure and Phase 2 Enzyme Inducer potencies, the intracellular concentrations (area under curve) correlated closely and linearly with their potencies as Inducers of the Phase 2 Enzymes: NAD(P)H:quinone reductase and glutathione S -transferases. Isothiocyanates that did not accumulate to high levels were not Inducers. These observations suggest strongly that induction of Phase 2 Enzymes depends on intracellular levels of isothiocyanates/dithiocarbamates. Depletion of glutathione by treatment of Hepa cells with buthionine sulfoximine increased the Inducer potencies of several isothiocyanates but could not be directly related to changes in intracellular isothiocyanate/dithiocarbamate concentrations, suggesting that glutathione may play several roles in the induction process.
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broccoli sprouts an exceptionally rich source of Inducers of Enzymes that protect against chemical carcinogens
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Jed W Fahey, Yuesheng Zhang, Paul TalalayAbstract:Abstract Induction of phase 2 detoxication Enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen. Since consumption of large quantities of fruit and vegetables is associated with a striking reduction in the risk of developing a variety of malignancies, it is of interest that a number of edible plants contain substantial quantities of compounds that regulate mammalian Enzymes of xenobiotic metabolism. Thus, edible plants belonging to the family Cruciferae and genus Brassica (e.g., broccoli and cauliflower) contain substantial quantities of isothiocyanates (mostly in the form of their glucosinolate precursors) some of which (e.g., sulforaphane or 4-methylsulfinylbutyl isothiocyanate) are very potent Inducers of phase 2 Enzymes. Unexpectedly, 3-day-old sprouts of cultivars of certain crucifers including broccoli and cauliflower contain 10–100 times higher levels of glucoraphanin (the glucosinolate of sulforaphane) than do the corresponding mature plants. Glucosinolates and isothiocyanates can be efficiently extracted from plants, without hydrolysis of glucosinolates by myrosinase, by homogenization in a mixture of equal volumes of dimethyl sulfoxide, dimethylformamide, and acetonitrile at −50°C. Extracts of 3-day-old broccoli sprouts (containing either glucoraphanin or sulforaphane as the principal Enzyme Inducer) were highly effective in reducing the incidence, multiplicity, and rate of development of mammary tumors in dimethylbenz(a)anthracene-treated rats. Notably, sprouts of many broccoli cultivars contain negligible quantities of indole glucosinolates, which predominate in the mature vegetable and may give rise to degradation products (e.g., indole-3-carbinol) that can enhance tumorigenesis. Hence, small quantities of crucifer sprouts may protect against the risk of cancer as effectively as much larger quantities of mature vegetables of the same variety.
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chemoprotection against cancer by phase 2 Enzyme induction
Toxicology Letters, 1995Co-Authors: Paul Talalay, Jed W Fahey, David W Holtzclaw, Tory Prestera, Yuesheng ZhangAbstract:Abstract Mammalian cells have evolved elaborate mechanisms for protection against the toxic and neoplastic effects of electrophilic metabolites of carcinogens and reactive oxygen species. Phase 2 Enzymes (e.g. glutathione transferase, NAD(P)H:quinone reductase, UDP-glucuronosyltransferases) and high intracellular levels of glutathione play a prominent role in providing such protection. Phase 2 Enzymes are transcriptionally induced by low concentrations of a wide variety of chemical agents and such induction blocks chemical carcinogenesis. The Inducers belong to many chemical classes including phenolic antioxidants, Michael reaction acceptors, isothiocyanates, 1,2-dithiole-3-thiones, trivalent arsenicals, HgCl2 and organomercurials, hydroperoxides, and vicinal dimercaptans. Induction by all classes of Inducers involves the antioxidant/electrophile response element (ARE/EpRE). Inducers are widely, but unequally, distributed among edible plants. Search for such Inducer activity in broccoli led to the isolation of sulforaphane, an isothiocyanate that is a very potent Phase 2 Enzyme Inducer and blocks mammary tumor formation in rats.
Jiankang Liu - One of the best experts on this subject based on the ideXlab platform.
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α tocopherol is an effective phase ii Enzyme Inducer protective effects on acrolein induced oxidative stress and mitochondrial dysfunction in human retinal pigment epithelial cells
Journal of Nutritional Biochemistry, 2010Co-Authors: Zhihui Feng, Haiqun Jia, Zhongbo Liu, Lijuan Sun, Chuan Tian, Lihong Jia, Jiankang LiuAbstract:Vitamin E has long been identified as a major lipid-soluble chain-breaking antioxidant in mammals. α-Tocopherol is a vitamin E component and the major form in the human body. We propose that, besides its direct chain-breaking antioxidant activity, α-tocopherol may exert an indirect antioxidant activity by enhancing the cell's antioxidant system as a Phase II Enzyme Inducer. We investigated α-tocopherol's inducing effect on Phase II Enzymes and its protective effect on acrolein-induced toxicity in a human retinal pigment epithelial (RPE) cell line, ARPE-19. Acrolein, a major component of cigarette smoke and also a product of lipid peroxidation, at 75 μmol/L over 24 h, caused significant loss of ARPE-19 cell viability, increased oxidative damage, decreased antioxidant defense, inactivation of the Keap1/Nrf2 pathway, and mitochondrial dysfunction. ARPE-19 cells have been used as a model of smoking- and age-related macular degeneration. Pretreatment with α-tocopherol activated the Keap1/Nrf2 pathway by increasing Nrf2 expression and inducing its translocation to the nucleus. Consequently, the expression and/or activity of the following Phase II Enzymes increased: glutamate cysteine ligase, NAD(P)H:quinone oxidoreductase 1, heme-oxygenase 1, glutathione S-transferase and superoxide dismutase; total antioxidant capacity and glutathione also increased. This antioxidant defense enhancement protected ARPE-19 cells from an acrolein-induced decrease in cell viability, lowered reactive oxygen species and protein oxidation levels, and improved mitochondrial function. These results suggest that α-tocopherol protects ARPE-19 cells from acrolein-induced cellular toxicity, not only as a chain-breaking antioxidant, but also as a Phase II Enzyme Inducer.
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polyhydroxylated fullerene derivative c60 oh 24 prevents mitochondrial dysfunction and oxidative damage in an mpp induced cellular model of parkinson s disease
Journal of Neuroscience Research, 2008Co-Authors: Xiaoqing Cai, Cheng Luo, Haiqun Jia, Zhongbo Liu, Bei Hou, Zhihui Feng, Jiankang LiuAbstract:To find effective agents for Parkinson's disease (PD) prevention and therapy, we examined the protective effects of the polyhydroxylated fullerene derivative C(60)(OH)(24) in a 1-methyl-4-phenylpyridinium (MPP(+)) -induced acute cellular PD model in human neuroblastoma cells and the free radical scavenging effects in this model with an electron spin resonance (ESR) spectrometer. Pretreatment with C(60)(OH)(24) at concentrations greater than 20 microM showed significant protective effects on MPP(+) -induced loss in cell viability, decreases in mitochondrial function (including mitochondrial membrane potential and activities of complex I and II), and increases in the levels of reactive oxygen species and oxidative damage to DNA and proteins. In addition, C(60)(OH)(24) acts as a phase 2 Enzyme Inducer to protect cells from MPP(+) -induced decreases in expression of nuclear factor-E2-related factor 2, expression and activity of gamma-glutamyl cysteine ligase and level of glutathione. The ESR study showed that C(60)(OH)(24) is a powerful radical scavenger for superoxide, hydroxyl, and lipid radicals. These data suggest that C(60)(OH)(24) is a mitochondrial protective antioxidant with direct radical scavenging activity and indirect antioxidant inducing activity.
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polyhydroxylated fullerene derivative c 60 oh 24 prevents mitochondrial dysfunction and oxidative damage in an mpp induced cellular model of parkinson s disease
Journal of Neuroscience Research, 2008Co-Authors: Xiaoqing Cai, Cheng Luo, Haiqun Jia, Zhongbo Liu, Bei Hou, Zhihui Feng, Jiankang LiuAbstract:To find effective agents for Parkinson's disease (PD) prevention and therapy, we examined the protective effects of the polyhydroxylated fullerene derivative C(60)(OH)(24) in a 1-methyl-4-phenylpyridinium (MPP(+)) -induced acute cellular PD model in human neuroblastoma cells and the free radical scavenging effects in this model with an electron spin resonance (ESR) spectrometer. Pretreatment with C(60)(OH)(24) at concentrations greater than 20 microM showed significant protective effects on MPP(+) -induced loss in cell viability, decreases in mitochondrial function (including mitochondrial membrane potential and activities of complex I and II), and increases in the levels of reactive oxygen species and oxidative damage to DNA and proteins. In addition, C(60)(OH)(24) acts as a phase 2 Enzyme Inducer to protect cells from MPP(+) -induced decreases in expression of nuclear factor-E2-related factor 2, expression and activity of gamma-glutamyl cysteine ligase and level of glutathione. The ESR study showed that C(60)(OH)(24) is a powerful radical scavenger for superoxide, hydroxyl, and lipid radicals. These data suggest that C(60)(OH)(24) is a mitochondrial protective antioxidant with direct radical scavenging activity and indirect antioxidant inducing activity.
Zhihui Feng - One of the best experts on this subject based on the ideXlab platform.
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coral calcium hydride prevents hepatic steatosis in high fat diet induced obese rats a potent mitochondrial nutrient and phase ii Enzyme Inducer
Biochemical Pharmacology, 2016Co-Authors: Chen Hou, Yongyao Wang, Erkang Zhu, Chunhong Yan, Lin Zhao, Xiaojie Wang, Yingfeng Qiu, Hui Shen, Xuejun Sun, Zhihui FengAbstract:Diet-induced nonalcoholic fatty liver disease (NAFLD) is characterized by profound lipid accumulation and associated with an inflammatory response, oxidative stress and hepatic mitochondrial dysfunction. We previously demonstrated that some mitochondrial nutrients effectively ameliorated high fat diet (HFD)-induced hepatic steatosis and metabolic disorders. Molecular hydrogen in hydrogen-rich liquid or inhaling gas, which has been confirmed in scavenging reactive oxygen species and preventing mitochondrial decay, improved metabolic syndrome in patients and animal models. Coral calcium hydride (CCH) is a new solid molecular hydrogen carrier made of coral calcium. However, whether and how CCH impacts HFD-induced hepatic steatosis remains uninvestigated. In the present study, we applied CCH to a HFD-induced NAFLD rat model for 13 weeks. We found that CCH durably generated hydrogen in vivo and in vitro. CCH treatment significantly reduced body weight gain, improved glucose and lipid metabolism and attenuated hepatic steatosis in HFD-induced obese rats with no influence on food and water intake. Moreover, CCH effectively improved HFD-induced hepatic mitochondrial dysfunction, reduced oxidative stress, and activated phase II Enzymes. Our results suggest that CCH is an efficient hydrogen-rich agent, which could prevent HFD-induced NAFLD via activating phase II Enzymes and improving mitochondrial function.
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α tocopherol is an effective phase ii Enzyme Inducer protective effects on acrolein induced oxidative stress and mitochondrial dysfunction in human retinal pigment epithelial cells
Journal of Nutritional Biochemistry, 2010Co-Authors: Zhihui Feng, Haiqun Jia, Zhongbo Liu, Lijuan Sun, Chuan Tian, Lihong Jia, Jiankang LiuAbstract:Vitamin E has long been identified as a major lipid-soluble chain-breaking antioxidant in mammals. α-Tocopherol is a vitamin E component and the major form in the human body. We propose that, besides its direct chain-breaking antioxidant activity, α-tocopherol may exert an indirect antioxidant activity by enhancing the cell's antioxidant system as a Phase II Enzyme Inducer. We investigated α-tocopherol's inducing effect on Phase II Enzymes and its protective effect on acrolein-induced toxicity in a human retinal pigment epithelial (RPE) cell line, ARPE-19. Acrolein, a major component of cigarette smoke and also a product of lipid peroxidation, at 75 μmol/L over 24 h, caused significant loss of ARPE-19 cell viability, increased oxidative damage, decreased antioxidant defense, inactivation of the Keap1/Nrf2 pathway, and mitochondrial dysfunction. ARPE-19 cells have been used as a model of smoking- and age-related macular degeneration. Pretreatment with α-tocopherol activated the Keap1/Nrf2 pathway by increasing Nrf2 expression and inducing its translocation to the nucleus. Consequently, the expression and/or activity of the following Phase II Enzymes increased: glutamate cysteine ligase, NAD(P)H:quinone oxidoreductase 1, heme-oxygenase 1, glutathione S-transferase and superoxide dismutase; total antioxidant capacity and glutathione also increased. This antioxidant defense enhancement protected ARPE-19 cells from an acrolein-induced decrease in cell viability, lowered reactive oxygen species and protein oxidation levels, and improved mitochondrial function. These results suggest that α-tocopherol protects ARPE-19 cells from acrolein-induced cellular toxicity, not only as a chain-breaking antioxidant, but also as a Phase II Enzyme Inducer.
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polyhydroxylated fullerene derivative c60 oh 24 prevents mitochondrial dysfunction and oxidative damage in an mpp induced cellular model of parkinson s disease
Journal of Neuroscience Research, 2008Co-Authors: Xiaoqing Cai, Cheng Luo, Haiqun Jia, Zhongbo Liu, Bei Hou, Zhihui Feng, Jiankang LiuAbstract:To find effective agents for Parkinson's disease (PD) prevention and therapy, we examined the protective effects of the polyhydroxylated fullerene derivative C(60)(OH)(24) in a 1-methyl-4-phenylpyridinium (MPP(+)) -induced acute cellular PD model in human neuroblastoma cells and the free radical scavenging effects in this model with an electron spin resonance (ESR) spectrometer. Pretreatment with C(60)(OH)(24) at concentrations greater than 20 microM showed significant protective effects on MPP(+) -induced loss in cell viability, decreases in mitochondrial function (including mitochondrial membrane potential and activities of complex I and II), and increases in the levels of reactive oxygen species and oxidative damage to DNA and proteins. In addition, C(60)(OH)(24) acts as a phase 2 Enzyme Inducer to protect cells from MPP(+) -induced decreases in expression of nuclear factor-E2-related factor 2, expression and activity of gamma-glutamyl cysteine ligase and level of glutathione. The ESR study showed that C(60)(OH)(24) is a powerful radical scavenger for superoxide, hydroxyl, and lipid radicals. These data suggest that C(60)(OH)(24) is a mitochondrial protective antioxidant with direct radical scavenging activity and indirect antioxidant inducing activity.
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polyhydroxylated fullerene derivative c 60 oh 24 prevents mitochondrial dysfunction and oxidative damage in an mpp induced cellular model of parkinson s disease
Journal of Neuroscience Research, 2008Co-Authors: Xiaoqing Cai, Cheng Luo, Haiqun Jia, Zhongbo Liu, Bei Hou, Zhihui Feng, Jiankang LiuAbstract:To find effective agents for Parkinson's disease (PD) prevention and therapy, we examined the protective effects of the polyhydroxylated fullerene derivative C(60)(OH)(24) in a 1-methyl-4-phenylpyridinium (MPP(+)) -induced acute cellular PD model in human neuroblastoma cells and the free radical scavenging effects in this model with an electron spin resonance (ESR) spectrometer. Pretreatment with C(60)(OH)(24) at concentrations greater than 20 microM showed significant protective effects on MPP(+) -induced loss in cell viability, decreases in mitochondrial function (including mitochondrial membrane potential and activities of complex I and II), and increases in the levels of reactive oxygen species and oxidative damage to DNA and proteins. In addition, C(60)(OH)(24) acts as a phase 2 Enzyme Inducer to protect cells from MPP(+) -induced decreases in expression of nuclear factor-E2-related factor 2, expression and activity of gamma-glutamyl cysteine ligase and level of glutathione. The ESR study showed that C(60)(OH)(24) is a powerful radical scavenger for superoxide, hydroxyl, and lipid radicals. These data suggest that C(60)(OH)(24) is a mitochondrial protective antioxidant with direct radical scavenging activity and indirect antioxidant inducing activity.