S. Dhakshinamoorthy⁽¹⁾, D. Bloom⁽²⁾, Anil Jaiswal^(3)
(1)(2)Department of Pharmacology. Baylor College of Medicine. - Houston. United States
⁽³⁾Baylor College of Medicine - Houston. United States

Antioxidants and their Mode of Action

Antioxidants are substances that either directly or indirectly protect cells against adverse effects of xenobiotics, drugs and carcinogens ^(1-5). Several biologically important compounds have been reported to have antioxidant functions. These include vitamin C (ascorbic acid), vitamin E, b-carotene, metallothionein, polyamines, melatonin, glutathione, superoxide dismutase and catalase ^(6-12). The antioxidant role of phenolic compounds including 3-( 2)-tert-butyl-4-hydroxyanisole (BHA), 3,5-di-tert-butyl-4-hydroxytoluene (BHT), and t-butyl hydroquinone (t-BHQ) in prevention of oxidative stress have been well documented ^(2-5). The various antioxidants either scavenge superoxide and free radicals or stimulate the detoxification mechanisms within cells resulting in prevention and increased detoxification of free radicals formation. Glutathione, superoxide dismutase and catalase directly scavenge superoxide, whereas BHA, BHT and t-BHQ coordinately induce the expression of a battery of genes, the products of which protect cells against oxidative stress and related consequences ^(13-21) (Fig. 1 and 2). Interestingly, many xenobiotics, oxidants, peroxides, UV light, and heavy metals also coordinately induce the expression of similar genes as observed with antioxidants (Fig. 1 and 2). Both, antioxidants and xenobiotics are metabolized by cellular enzymes to generate superoxide and electrophiles. It is believed that this initial generation of superoxide is to activate a battery of genes for cellular protection. Failure in this mechanism leads to the accumulation of superoxide and other free radicals. The accumulation of superoxide and other free radicals is known to cause oxidative stress, DNA and membrane damage, mutagenicity, degeneration of tissues, premature aging, apoptotic cell death, cellular transformation and cancer ^(13-21). This article focuses on the mechanisms by which antioxidants and xenobiotics induce the gene expression of detoxifying enzyme.

Induction of Genes Encoding Enzymes that Detoxify Xenobiotics and Carcinogens.

The expression and induction of enzymes that metabolize xenobiotics, drugs and carcinogens play an important role in determining the risk of cancer in human ^(13-21). In other words, the development of chemically induced neoplasia is regulated by a balance between phase I (cytochromes P450, cytochrome P450 reductase, hydroxylases, lipoxygenases, peroxidases and oxidases), which activate carcinogens, and phase II (detoxifying/chemopreventive) enzymes, which detoxify them. The phase II (detoxifying) enzymes include NAD(P)H:Quinone Oxidoreductases (NQOs), which catalyze obligatory two-electron reduction of quinones and their derivatives thus preventing their participation in redox cycling and oxidative stress ^(13-17); glutathione S-transferases (GSTs), which conjugate hydrophobic electrophiles and reactive oxygen species with glutathione (GSH) ^(18-21); UDP-glucuronosyl transferases (UDP-GT), which catalyze the conjugation of glucuronic acid with xenobiotics and drugs for their excretion ⁽²²⁾; epoxide hydrolase (EH), which inactivates epoxides ⁽²³⁾; g-glutamylcysteine synthetase (g-GCS), which plays a key role in the regulation of glutathione metabolism ⁽⁶⁾ and so on.

Among the various detoxifying enzymes, the NQOs and the GSTs have been extensively studied. The NQO gene family contains two members designated as NQO1 and NQO2 ^(15-17). Mutations in the NQO1 gene resulting in the loss of NQO1 enzyme activity have been reported in certain types of cancers ^(24-30). Various GSTs including the GST Ya and GST P genes are encoded by five gene families ⁽²⁰⁾. Loss of GSTs are associated with several kinds of cancer. This includes prostate, urothelial, lung and colorectal cancer ^(31-34).

In addition to the detoxification enzymes, several other enzymes also protect cells from oxidative stress by preventing the generation of superoxide or by scavenging superoxide. These enzymes include heme oxygenase-1 (HO-1), superoxide dismutase-1 (SOD-1; also referred to as Cu/Zn SOD) and catalase ^(35-37). HO-1 increases the intracellular levels of ferritin ⁽³⁵⁾. The increase in ferritin limits the availability of iron to catalyze harmful reactions, such as the peroxidation of lipids and the fenton reaction producing hydroxyl radicals thus, protecting the cells against UV induced oxidative stress.

Studies have revealed that the capacity of many diverse chemicals to block carcinogenesis correlates with their capacity to induce NQO1 and other detoxifying enzymes including GSTs ⁽¹³⁾. Induction of NQO1 and GST by Sulforaphane from Saga broccoli blocks the formation of mammary tumors in Sprague-Dawley rats treated with single dose of 9,10 dimethyl-1,2-benzanthracene ⁽³⁸⁾.

The Genes encoding the human and rat NQO1, human NQO2, rat GST Ya and rat GST P were cloned and sequenced ^(39-44). Among these genes, the regulation of NQO1 and GST Ya expression is best studied. The NQO1 and GST Ya genes are expressed at higher levels in liver tumors and tumor cells as compared to normal liver and liver hepatocytes. These genes are coordinately induced in response to xenobiotics and antioxidants ^(17,20,45).

Antioxidant Response Element

Deletion mutagenesis studies of the human NQO1 gene promoter identified several cis-elements that are essential for the expression and induction of the NQO1 gene ^(46-50,17). One of these elements was 24 base pairs of the antioxidant response element (ARE) that are required for basal expression as well as induction of NQO1 gene in response to b-naphthoflavone (b-NF), 2⁽³⁾-tert-butyl-4-hydroxy-anisole (BHA), tert-butylhydroquinone (tBHQ) and hydrogen peroxide. Other elements include a DNA fragment (between -780 to -365) that is required for TCDD induction of NQO1 gene expression; a basal element (region between -130 to -47) and an AP2 element (at nucleotide position -157) essential for cAMP induced expression of the NQO1 gene. ARE-like elements have also been found in the promoter regions of the rat NQO1 gene ⁽⁵¹⁾; the human NQO2 gene ⁽⁴¹⁾; the rat and mouse glutathione S-transferase Ya (GST Ya) subunit genes ^(52-55), the rat glutathione S-transferase P gene ⁽⁵⁶⁾ and g-glutamyl cysteinyl synthetase gene ⁽⁵⁷⁾ (Fig. 3). The conservation of the ARE in the genes of many detoxifying enzymes indicated that these genes may be coordinately regulated by a single mechanism involving ARE (58; Fig. 3). The NQO1 gene ARE contains one perfect and one imperfect TRE (TPA response element) arranged as inverse repeats separated by three base pairs followed by a ´GC´ box (58, Fig.3). The nucleotide sequence analysis of the other gene AREs also revealed that they contain TRE/TRE-like elements arranged as inverse or direct repeats. These repeats are separated by three or eight nucleotides, followed by a GC box ⁽⁵⁸⁾. The seven base pairs TRE was characterized previously in the promoter regions of the collagenase and metallothionein genes, and is required to activate expression of these genes in response to TPA ⁽⁵⁹⁾. The human NQO1 gene ARE and other detoxifying enzyme gene AREs are unique cis-elements even though they contain TRE and TRE-like elements. This is because it is ARE, rather than TRE, that is responsive to antioxidants and xenobiotics ⁽⁵⁸⁾. Mutational analysis of the ARE identified GTGAC***GC as the core of the ARE sequence ^(49,53) (Fig. 3). Additional cis-element and nucleotide sequences flanking the core sequence have been shown to contribute to the ARE-mediated expression and induction ^(49,60-62).

Antioxidant Response Element-Binding Proteins

Nuclear transcription factors c-Jun, Jun-B, Jun-D, c-Fos, Fra1, Nrf1, Nrf2, YABP, ARE-BP1, Ah (aromatic hydrocarbon) receptor and the estrogen receptor have been reported to bind to the AREs from various genes (46-48, 63; 54-55, 62, 64-67). Among these transcription factors, c-Jun, Jun-B, Jun-D, c-Fos, Fra1, Nrf1 and Nrf2 bind to the human NQO1 gene ARE (46-48; 63) (Fig. 4). Nrf1 and Nrf2 have been shown to positively regulate the ARE-mediated expression and induction of NQO1 gene in response to antioxidants and xenobiotics (63; Fig. 5). Nrf1 and Nrf2 are b-zip (leucine zipper) proteins that do not heterodimerize with each other and require another leucine zipper protein for its activity ^(68-69). Recently, Nrf2-/- mice lacking the expression of Nrf2 were generated ⁽⁷⁰⁾. These mice showed significantly reduced expression and induction of NQO1 gene indicating a physiological (in vivo) role of transcription factor Nrf2 in the regulation of expression of NQO1 gene ⁽⁷⁰⁾. More recently, nuclear transcription factors Nrf1 and Nrf2 have been demonstrated to heterodimerize with c-Jun, Jun-B and Jun-D proteins to upregulate ARE-mediated expression and coordinated induction of detoxifying enzymes in response to antioxidants and xenobiotics (71; Fig. 6). Nrf2 containing one mutated leucine in its leucine zipper region was more efficient in upregulation of ARE-mediated gene expression, as compared to Nrf1 with two mutated leucines ⁽⁷¹⁾. Interestingly, Nrf-Jun association/heterodimerization and binding to the ARE required unknown cytosolic factor(s) ⁽⁷¹⁾. The identity of cytosolic factor(s) remains unknown.

Alignment of DNA binding regions of Nrf1 and Nrf2 with the Jun (c-Jun, Jun-B and Jun-D) proteins revealed the presence of highly conserved, redox labile, cysteine residue in the ´Basic region´. The alignment also revealed several conserved leucines in the leucine zipper regions (Fig.7). Of particular interest are two leucines (# 4 and 5) in the leucine zipper region of Nrf1 and one leucine (#4) in Nrf2. When compared to Jun proteins, these leucines were found to be mutated. These differences may be responsible for the variation in their capacity to mediate ARE-regulated gene expression ⁽⁶³⁾.

It has been suggested that overexpression of c-Fos and Fra1 in transfected Hep-G2 cells repressed the ARE-mediated gene expression (63; Fig. 8). The negative role of c-Fos in ARE-mediated expression has also been observed in c-Fos-/- mice (72; Fig. 8). c-Fos-/- mice showed increased expression of NQO1 and GST Ya as compared to wild type c-Fos+/+ mice (72; Fig. 8). Therefore, it appears that ARE-mediated expression of detoxifying enzyme genes is balanced by positive and negative regulatory factors. One hypothesis is that small amounts of superoxide and related reactive species are consistently required for keeping cellular defenses active. Since activation of detoxifying enzymes and other defensive proteins leads to significant reduction in the levels of superoxide and other free radicals, the cell may require negative regulatory factors like c-Fos to keep the expression of detoxifying enzymes and other defensive genes "in check".

Recently, a 74.3 kDa protein designated as YABP has been shown to bind to the GST Ya gene ARE ⁽⁶⁴⁾. At present it is not clear if YABP is related to the 65 kDa Nrf1 and 68 kDa Nrf2 proteins, or represents a new class of protein(s).

Recent studies in our and other laboratories have identified a inhibitory protein that retains the Nrf2 in the cytoplasm (S. Dhakshinamoorthy and A. K. Jaiswal, Unpublished; reference 73). We have cloned this protein from rat liver cytosol. This protein was designated by us as ´Inhibitor of Nrf2 or INrf2´. The peptide sequence of INrf2 is shown in Fig. 9. INrf2 is highly homologous to mouse and human Keap1 and Drosophila kelch protein. The various results have shown that INrf2 retains Nrf2 in the cytoplasm. The treatment of cells with xenobiotics and antioxidants releases Nrf2 from Inrf2 (data not shown). The free Nrf2 moves into the nucleus, heterodimerizes with c-Jun and binds to ARE that regulates expression and induction of NQO1 and other detoxifying enzyme genes. The mechanism of dissociation of Nrf2 from Inrf2 remains unknown. Rat, mouse and human INrf2/Keap1 are cysteine rich proteins (Fig. 9). The various cysteins were found highly conserved among the three proteins.

More recently, hMAF, a small human transcription factor was shown to homodimerize and heterodimerize with Nrf1 and Nrf2 ⁽⁷⁴⁾. Although hMAF-hMAF homodimers and hMAF/Nrf1 and hMAF/Nrf2 heterodimers bind to the similar NF-E2 binding site, yet they exert functionally opposite effects. hMAF homodimers represses b-globin gene expression whereas hMAF heterodimerization with Nrf1 and Nrf2 activates b-globin gene expression. Since, hMAF heterodimerizes with Nrf1 and Nrf2, its role in the regulation of Nrf+c-Jun regulated hARE-mediated expression of detoxifying enzyme genes remains to be determined. Recently, an Nrf2-MafK heterodimer was shown to bind to the ARE of a gene encoding a subunit of GST Ya. This suggests that the Nrf2-MafK heterodimer may play a role in the ARE-mediated induction of GST Ya gene expression ⁽⁷⁰⁾. However, the regulatory role of MafK in Nrf/Jun regulation of ARE-mediated expression of NQO1 gene remains unknown.

Mechanism of Signal Transduction for ARE-mediated expression and induction of NQO1 gene

The various steps in the mechanism of signal transduction from antioxidants and xenobiotics to the Nrf1, Nrf2, Jun and Fos proteins that bind to the ARE and regulate ARE-mediated basal expression and coordinated induction of the various detoxifying enzyme genes remains unknown. A hypothetical model showing ARE-mediated induction of NQO1 and other detoxifying enzyme genes expression in response to xenobiotics and antioxidants is shown (Fig. 10). Xenobiotics and antioxidants undergo metabolism to generate superoxide and electrophiles ⁽⁷⁵⁾. The generation of superoxide and related species is a common phenomenon between antioxidants and xenobiotics. For this reason, superoxide is believed to serve as signal that activates a battery of defensive genes including NQO1 that protect cells against the adverse effects of oxidative stress. Recently, the quinone-mediated generation of hydroxyl radicals were reported to induce the ARE-mediated expression of the mouse glutathione S-transferase gene ⁽⁷⁶⁾. This correlation remains unknown in the case of AREs from other genes including NQO1. Hydrogen peroxide, however, has been demonstrated to induce the ARE-mediated expression of rat GST Ya, rat NQO1 and human NQO1 genes ^(77-78). Hence, it may be an important intermediate in the induction of these genes by the antioxidants and xenobiotics. The role of electrophiles, if any, in the ARE mediated expression and induction of detoxifying enzyme genes remains unknown.

The superoxide signal presumably passes either directly or through unknown intermediary proteins, to the cytosolic factor(s) (Fig. 10). The cytosolic factor(s) catalyze modification of Nrf2 leading to the dissociation of Nrf2 from INrf2/Keap1. Nrf2 translocates in the nucleus. Alternatively, cytosolic factor(s) catalyze modification of INrf2/Keap1 resulting in dissociation of Nrf2 from INrf2/Keap1. This follows the translocation of Nrf2 in the nucleus. The modifications of Nrf2 and/or INrf2/Keap1 by cytosolic factor(s) are expected because the treatment of cells with xenobiotics and antioxidants do not alter the expression of genes encoding Nrf2 and Keap1 (S. Dhakshinamoorthy, V. Radjendirane and A.K. Jaiswal, unpublished). Nrf2 after translocation in the nucleus forms heterodimer with c-Jun which binds to the ARE resulting in the induction of NQO1 and other ARE-regulated genes expression. c-Jun may also undergo some modifications by cytosolic factor(s) before moving to the nucleus for heterodimerization with Nrf2. However, this is less likely because the transcription of c-Jun gene is significantly increased in response to xenobiotics and antioxidants. Nrf1 is expected to function in a similar manner as Nrf2. The Jun-B and Jun-D may function similar as c-Jun. This is because of their role in ARE-mediated expression and induction of NQO1 gene expression ⁽⁷⁰⁾.

The identification of the unknown cytosolic factor(s) in the stimulation of Nrf+Jun binding to the ARE is an important step to our understanding of the signal transduction pathway from endogenous substances, xenobiotics and antioxidants to the Nrf+Jun proteins. However, the nature of the cytosolic factor(s) remains unknown. The unknown cytosolic factor(s) may be a kinase/phosphatase or redox protein(s) that catalyzes the necessary modification of Nrf and/or Jun proteins to stimulate their binding to the ARE. Previous studies have demonstrated increased binding of nuclear factors to the ARE and increased expression of ARE-mediated CAT gene expression in response to dithiothretol and b-mercaptoethanol ⁽⁷⁸⁾. This suggests that the unknown cytosolic factor(s) may be redox protein(s). It is also supported by studies of transcription factors OxyR and SoxRS that protect bacterial cells against oxidative stress by inducing a group of defensive genes ^(79-80). The regulation of OxyR has been shown to involve oxidation and reduction of cysteine residues ⁽⁸¹⁾. However, the identification of the unknown cytosolic factor(s) as kinase(s)/phosphatase(s) could not be ruled out. The cytosolic factor(s) may serve as sensors of oxidative stress which receive signal from superoxide and related species and then pass it to the oxidative stress responsive factors, Nrf-Jun. This, in turn, leads to increased expression of ARE containing detoxifying and other defensive proteins.

Summary and Conclusions

Antioxidants are substances that delay or prevent the oxidation of cellular oxidizable substrates. The various antioxidants exert their effect by scavenging superoxide, or by activating of a battery of detoxifying/defensive proteins. In this article, we have focused on the mechanisms by which antioxidant induce gene expression. Many xenobiotics (e. g. b-naphthoflavone) activate the similar genes as antioxidants. The promoters of these genes contain a common cis-element designated as ´Antioxidant Response Element´ or ´ARE´. The ARE contains two TRE (TPA response element) or TRE-like elements followed by ´GC´ box. Mutational studies identified GTGAC***GC as core of the ARE sequence. Many transcription factors including Nrf, Jun, Fos, Fra, Maf, YABP, ARE-BP1, Ah (aromatic hydrocarbon) receptor and estrogen receptor bind to the ARE from the various genes. Among these factors, Nrf-Jun heterodimers positively regulate ARE-mediated expression and induction of genes in response to antioxidants and xenobiotics. This Nrf-Jun heterodimerization and binding to the ARE requires unknown cytosolic factors.

The mechanism of signal transduction from antioxidants and xenobiotics includes several steps, 1) Antioxidants and xenobiotics undergo metabolism to generate superoxide and related reactive species leading to the generation of a signal to activate detoxifying/defensive genes expression; 2) The generation of superoxide and related reactive species is followed by activation of yet to be identified cytosolic factor(s), by unknown mechanism(s); 3). Activated cytosolic factor(s) catalyze modification of Nrf2 and/or INrf2 4) Release of Nrf2 from INrf2 followed by nuclear localization of Nrf2 to the nucleus; 5) Transcriptional activation and modification? of c-Jun; 6) Heterodimerization of Nrf2 with c-Jun; 7) Binding of Nrf2-c-Jun complex to the ARE from the various detoxifying enzyme genes; and 8) The coordinated increased transcription of genes encoding detoxifying/defensive proteins. In this mechanism Nrf1 is expected to behave same as Nrf2 and Jun-B and Jun-D proteins same as c-Jun. The unknown cytosolic factor(s) are significant molecules because they represent the oxidative sensors within the cells. Identification of the cytosolic factor(s) will be of considerable importance in the field of antioxidants and gene regulation research. Future studies will also be required to completely understand the molecular mechanism of signal transduction from antioxidants and xenobiotics to Nrf-Jun. In addition to Nrf-Jun pathway, the mammalian cells also contain other pathways that activate gene expression in response to oxidative stress. These include NF-KB, HIF-1 Mac-1 and SRF mediated pathways. It is expected that collectively these pathways increase transcription of more than four dozen genes to protect cells against oxidative stress.

Acknowledgements

We thank our colleagues for helpful discussion. This investigation was supported by NIH grant GM47466.

References

Halliwell, B. (1995). Biochem. Pharm. 49, 1341-1348.
Wattenberg, L.W. (1972). J. Natl. Cancer Inst. 48, 1425-1430.
Ulland, B.M., Weisburger, J.H., Yamamoto, R.S., Weisburger, E.K. (1973). Food Cosmet. Toxicol. 11, 199-207.
Kahl, R. (1984). Toxicology 33, 185-228.
Talalay, P. (1989). Adv. Enzyme Regul. 28, 149-159.
Meister, A. (1994). J. Biol. Chem. 269, 9397-9400.
Halliwell, B., and Gutteridge, J.M.C. (1989). In "Free Radicals in Biology and Medicine" Clarendon Press, Oxford.
Halliwell, B. (1990). Free Radic. Res. Commun. 9, 1-32.
Sies H. (1985). In " Oxidative Stress" Academic Press, New York.
Gutteridge, J.M.C., and Stocks, J. (1981). Crit. Rev. Clin. Lab. Sci. 14, 257-329.
Diplock, A.T. (1981). In "Fat-Soluble Vitamins" (A.T. Diplock, ed.), pp 154-224, Heinemann, London.
Fridovich, I. (1989). J. Biol. Chem. 264, 7761-7764.
Talalay, P., Fahey, J.W., Holtzclaw, W.D., Prestera, T., and Zhank, Y. (1995). Toxicol. Lett. 82-83, 173-179.
Riley, R.J., and Workman, P. (1992). Biochem. Pharm. 43, 1657-1669.
Belinsky, M., and Jaiswal, A.K. (1993). Cancer Metastasis Reviews 12, 103-117.
Joseph, P., Xie, T., Xu, Y., and Jaiswal, A.K. (1994). Oncol. Res. 6, 525-532, 1994.
Radjendirane, V., Joseph, P., and Jaiswal, A.K. (1997). In ´OXIDATIVE STRESS AND SIGNAL TRANSDUCTION´ (E. Cadenas and H. J. Forman), pp 441-469, Chapman and Hall, New York.
Pickett, C.B., and Lu, A.Y.H. (1989). Ann. Rev. Biochem. 58, 743-764.
Tsuchida, S., and Sato, K. (1992). Crit. Rev. in Biochem. and Mole. Biol. 27, 337- 384.
Rushmore, T.H., and Pickett, C.B. (1993). J. Biol. Chem. 268, 11475-11478.
Daniel, V. (1993). Crit. Rev. in Biochem. and Mole. Biol. 28, 173-207.
Tephly, T., and Burchell, B. (1990). Trends in Pharm. 11, 276-279.
Oesch, F., Gath, I., Igarashi, T., Glatt, H.R., and Thomas, H. (1991).In "Molecular Aspects of Monooxygenases and Bioactivation of Toxic Compounds" (E. Arinc, J.B. Schenkman and E. Hodgson eds.), pp 447-461 Plenum Press, New York.
Traver, R.D., Horikoshi, T., Danenberg, K.D., Stadlbauer, T.H.W., Danenberg, P.V., Ross, D.,and Gibson, N.W. (1992). Cancer Res. 52, 797-802.
Rosvold, E.A., McGlynn, K.A., Lustbader, E.D., and Buetow, K.H. (1995). Pharmacogenetics 5, 199-206.
Eickelmann, P., Schulz, W.A., Rohde, D., Schmitz-Drager, B., and Sies, H. (1994). Biol. Chem. Hoppe-Seyler 33, 439-445.
Kolesar, J.M., and Kuhn, J.G. (1995). J. Natl. Can. Inst. 87, 1022-1024.
Kuehl, B.L., Paterson, J.W.E., Peacock, J.W., Paterson, M.C., and Rauth, A.M. (1995). Br. J. Cancer 72, 555-561.
Lee, W.H., Morton, R.A., Epstein, J.I., Brooks, J.D., Campbell, P.A., Bova, G.S., Hsieh, W.S., Isaacs, W.B., and Nelson, W.G. (1994) Proc. Natl. Acad. Sci. USA 91, 11733-11737.
Rauth, A.M., Goldberg, Z., and Misra, V. (1997). Oncol. Res. 9, 351-356.
Katoh, T., Inatomi, H., Nagaoka, A., and Sugita, A. (1995). Carcinogenesis 16, 655- 657.
Anttila, S., Luostarinen, L., Hirvonen, A., Elovaara, E., Karjalainen, A., Nurminen, T., Hayes, J.D., Vainio, H., and Ketterer, B. (1995). Cancer Res. 55, 3305-3309.
Lin, H.J., Probst-Hensch, N.M., Ingles, S.A,, Han, C., Lin, B.K., Lee, D.B., Frankl, H.D., Lee, E.R., Longnecker, M.P., and Haile, R.W. (1995). Cancer Res. 55, 1224- 1226.
Mulder, T.J., Verspaget, H.W., Sier, C.F.M., Roelofs, H.M.J., Ganesh, S., Griffioen, G., Peters, W.H.M. (1995). Cancer Res. 55, 2696-2702.
Vile, G.F., Basu-Modak, S., Waltner, C., and Tyrrell, R.M. (1994). Proc. Natl. Acad. Sci. USA 91, 2607-2610.
Mischiels, C., Raes, M., Toussaint, O., and Remacle, J. (1994). Free Radical Biology & Medicine 17, 235-248.
Yasmineh, W.G., Theologides, A. (1993). J. Lab. & Clin. Med. 122, 110-114.
Zhang, Y., Kensler, T.W., Cho, C., Posner, G.H., and Talalay, P. (1994). Proc. Natl. Acad. Sci. USA 91, 3147-3150.
Jaiswal, A.K. (1991) Biochemistry 30, 10647-10653.
Bayney, R.M., Morton, M.R., Favreau, L.V., and Pickett, C.B. (1989). J. Biol. Chem. 264, 21793-21797.
Jaiswal, A.K. (1994). J. Biol. Chem. 269, 14502-14508.
Telakowski-Hopkins, C.A., Rothkopf, G.S., and Pickett, C.B. (1986). Proc. Natl. Acad. Sci. USA 83, 9393-9397.
Telakowski-Hopkins, C.A., King, R.G., Pickett, C.B. (1988). Proc. Natl. Acad. Sci. USA 85, 1000-1004.
Sakai, M., Okuda, A., and Muramatsu, M. (1988). Proc. Natl. Acad. Sci. USA 85, 9456-9460.
Talalay, P., De Long, M.J. and Prochaska, H. (1988). Proc. Natl. Acad. Sci. USA 85, 8261-8265.
Li, Y., Jaiswal, A.K. (1992). J. Biol. Chem. 267, 15097-15104.
Li, Y., and Jaiswal, A.K. (1992). Biochem. Biophys. Res. Commun. 188, 992-996.
Li, Y., and Jaiswal, A.K. (1994). Europ. J. Biochem. 226, 31-39.
Xie, T., and Jaiswal, A.K. (1996). Biochem. Pharm. 51, 771-778.
Favreau, L.V., and Pickett, C.B. (1991). J. Biol. Chem. 266, 4556-4561.
Rushmore, T.H., King, R.G., Paulson, K.E., and Pickett, C.B. (1990). Proc. Natl. Acad. Sci. USA 87, 3826-3830.
Rushmore, T.H., and Pickett, C.B. (1990). J. Biol. Chem. 265, 14648-14653.
Rushmore, T.H., Morton, M.R., and Pickett, C.B. (1991). J. Biol. Chem. 266, 11632- 11639.
Friling, R.S., Bensimon, A., Tichauer, Y., and Daniel, V. (1990). Proc. Natl. Acad. Sci. USA 87, 6258-6262.
Friling, R.S., Bergelson, S., and Daniel, V. (1992). Proc. Natl. Acad. Sci. USA 89, 668-672.
Okuda, A., Imagawa, M., Maeda, Y., Sakai, M., and Muramatsu, M. (1990). The EMBO Journal 9, 1131-1135.
Mulkahy, R.T., Wartman, M.A., Bailey, H.H., Gipp, J.J. (1997). J. Biol. Chem. 272, 7445-7454.
Jaiswal, A.K. (1994). Antioxidant response element. Biochem. Pharmacol. 48, 439- 444.
Angel, P., and Karin, M. (1991). Biochem. et Biophys. Acta 1072, 129-157.
Prestera, T., Holtzclaw, W.D., Zhang, Y. and Talalay, P. (1993). Proc. Natl. Acad. Sci. USA 90, 2965-2969.
Bergelson, S., Pinkus, R., and Daniel, V. (1994). Oncogene 9, 565-571.
Wasserman, W., and Fahl, W.E. (1997). Proc. Natl. Acad. Sci. USA. 94, 5361-5366.
Radjendirane, V., and Jaiswal, A.K. (1996). Proc. Natl. Acad. of Sci. USA 93, 14960- 14965.
Liu, S., and Pickett, C.B. (1996). Biochemistry 35, 11517-11521.
Vasliou, V., Puga, A., Chang, C., Tabor, M.W., and Nebert, D.W. (1995). Biochem. Pharm. 12, 2057-2068.
Yoshioka, K., Deng, T., Cavigelli, M., and Karin, M. (1995). Proc. Natl. Acad. Sci. USA 92, 4972-4976.
Montano, M.M., Jaiswal, A.K., and Katzenellenbogen, B.S. (1998). J. Biol. Chem. 273, 25443-25449.
Chan, J.Y., Han, X., and Kan, Y.W. (1993). Proc. Natl. Acad. Sci. USA 90, 11371- 11375.
Moi, P., Chan, K., Asunis, I., Cao, A., and Kan, Y.W. (1994). Proc. Natl. Acad. Sci. USA 91, 9926-9930.
Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, K., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., Yamamoto, M., and Y Nabeshima. (1997). Biochem. Biophys. Res. Commun. 236:313-322.
Radjendirane, V., and Jaiswal, A.K. (1998). Oncogene 17, 3145-3156.
Wilkinson, J., Radjendirane, V., Pfeiffer, G.R., Jaiswal, A.K., and Clapper, M.L. (1998). Biochem. Biophys. Res. Commun. 253, 855-858.
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J.D., and Yamamoto, M. (1999). Genes & Dev. 13, 76-86.
Marini, M.G., Chan, K., Casula, L., Kan, Y.W., Cao, A., and Moi, P. (1997). J. Biol. Chem. 272, 16490-16497.
De Long, M.J., Santamaria, A.B., and Talalay, P. (1987). Carcinogenesis 8, 1549- 1553.
Pinkus, R., Weiner, L.M., and Daniel, V. (1996). J. Biol. Chem. 271, 13422-13429.
Favreau, L.V., and Pickett, C.B. (1991). J. Biol. Chem. 266, 4556-4561.
Li, Y., and Jaiswal, A.K. (1994). Eur. J. Biochem. 226, 31-39.
Demple, B., and Amabile-Cuevas, C.F. (1991). Cell 67,837-839.
Meyer, M., Schreck, R., and Baeuerle, P. (1993). The EMBO J. 12, 2005-2015.
Zheng, M., Aslund, F., and Storz, G. (1998). Science 279, 1718-1721.

Discussion Board

Any Comment to this presentation?

[ABSTRACT] [Antioxidants and their Mode of Action] [Induction of Genes Encoding Enzymes that Detoxify Xenobiotics and Carcinogens.] [Antioxidant Response Element] [Figures] [Figures-2] [Antioxidant Response Element-Binding Proteins] [Summary and Conclusions] [Acknowledgements] [References] [Discussion Board]

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S. Dhakshinamoorthy, D. Bloom, Anil Jaiswal
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Last update: 24/01/00