Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Cytochrome-P450 enzymes and autoimmunity: expansion of the relationship and introduction of free radicals as the link

Cytochrome-P450 enzymes and autoimmunity: expansion of the relationship and introduction of free... The Cytochrome-P-450 enzymes (CYP) are among the most important xenobiotic-metabolizing enzymes, which produce reactive oxygen species (ROS) as the result of metabolizing xenobiotics. ROS are believed to play important roles in the pathophysiology of autoimmune diseases. ROS can alter the structure of cellular antigens to produce a "neo-antigen" which could mount an autoimmune response against the original antigen through molecular mimicry. ROS are involved in apoptosis, activation of antigen presenting cells and initiation or amplification of diverse immunologic reactions. Taking all these facts together, it could be speculated that CYP may be involved in the initiation and/or amplification of autoimmune phenomena. "Who is in me, heart-weary, now I know not: the readers to the ability of CYP to induce/amplify autoimmunity through production of free radicals. While I am mute, a voice within me roars..." Presentation of the hypothesis Hafez Shirazi (a great Persian Poet) a) Brief description of CYP enzymes and their involvement in the production of reactive oxygen species (ROS) Background Upon entering the body, a foreign compound is subjected Involvement of cytochrome P450 (CYP) enzymes in the to metabolism by a large group of enzymes, collectively pathogenesis of autoimmune hepatitis type 2, occurring referred as xenobiotic-metabolizing enzymes. Although via molecular mimicry of human cytochrome P450 by originally thought to be responsible for drug metabolism hepatitis C virus at the level of cytotoxic T cell recognition, almost exclusively in the liver, it has now been realized is well appreciated [1]. In addition, two different cyto- that all xenobiotic-metabolizing enzymes participate in chrome P450 enzymes are believed to be the adrenal anti- many crucial endogenous functions, probably in every gens in autoimmune polyendocrine syndrome type I and eukaryotic cell and many prokaryotes. The CYP enzymes Addison's disease [2]. However, except these two diseases are among the most important xenobiotic-metabolizing where CYP serves as the autoantigen and hence functions enzymes and are the products of the CYP superfamily of as the core of the autoimmunity, the potential contribu- genes [3]. They are embedded in the phospholipids tion of CYP in autoimmune diseases has not been investi- bilayer of the endoplasmic reticulum [4]. gated. It is attempted in this paper to draw the attention of Page 1 of 5 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:4 http://www.jautoimdis.com/content/6/1/4 CYPs are named with the root CYP followed by a number olism of bile acids, which are degradation by-products of designating the family, a letter denoting the subfamily, cholesterol. Some CYPs, such as those that catalyze steroid and another number designating the CYP form. Thus, and bile acid synthesis, have very specific substrate prefer- CYP3A4 is family 3, subfamily A, and gene number 4. All ences [4]. CYPs contain a molecule of heme that is noncovalently bound to the polypeptide chain. Metabolism of a sub- The liver contains the greatest abundance of xenobiotic- strate by CYP consumes one molecule of molecular oxy- metabolzing CYPs. More than 50 individual CYP have gen and produces an oxidized substrate plus a molecule of been identified in humans, of which 12 are known to be water as a by-product. However, for most CYPs, depend- important for metabolism of xenobiotics. The expression ing on the nature of the substrate, the reaction is "uncou- of different CYPs can differ markedly through interindi- pled", consuming more O than the metabolized vidual changes resulting from heritable polymorphic dif- substrate and producing activated oxygen or O [4]. CYPs ferences in gene structure. Several human CYP genes metabolize most clinically used drugs and are required for exhibit polymorphisms, including CYP2A6, CYP2C9, metabolic activation of chemical carcinogens and toxins CYP2C19, and CYP2D6 [4]. [5]. Additionally, CYPs are involved in the synthesis of endogenous compounds such as steroids and the metab- Genera Figure 1 tion of ROS by CYP .- Generation of ROS by CYP. Cells generate ROS such as superoxide anion (O ) and H O as a result of metabolism of 2 2 2 .- .- 2+ xenobiotics by CYP. Both O and H O may be converted to the highly reactive hydroxyl radical (OH ) by iron (Fe )-cata- 2 2 2 lyzed Haber-Weiss and Fenton reactions. Many xenobiotics are converted to toxic quinones by CYP. These quinones are .- redox-sensitive agents and are reversibly reduced to semihydroquinones/hydroquinones, which generate O . Page 2 of 5 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:4 http://www.jautoimdis.com/content/6/1/4 Many xenobiotics are converted to toxic quinones by CYP vation of sentinel dendritic cells, linking tissue damage to enzymes (Figure 1). These quinones are redox sensitive initiation of an immune response [9,14]. Addition of agents and are reversibly reduced to semihydoquinones/ DNFB, a strong skin sensitizer, to a dendritic cell line gen- hydroquinone, which generate superoxide anion. Both erated from fetal mouse skin enhanced protein oxidation superoxide anion and hydrogen peroxide may be con- and induced p38 MAPK and extracellular signal-regulated 2+ verted to hydroxyl radical by iron (Fe )-catalyzed Haber- kinase (ERK)1/2 phosphorylation, which could be Weiss and Fenton reactions [6]. Theses reactive molecules blocked by GSH [15]. are more often derived from foreign chemicals (for exam- ple, insecticides) than from endogenous substrates (for Reactive oxygen species activate NF-κB through activation example, lipid peroxides) [7]. of kinases [16]. On activation, NF-κB regulates the expres- sion of almost 400 different genes, which include b)The important role of ROS in the pathogenesis of autoimmunity enzymes such as iNOS, cytokines (such as TNF-α, IL-1 and There are several ways by which ROS could contribute to chemokines), and adhesion molecules [9,17]. the development of autoimmunity. These mechanisms, also discussed fully in reference [9], are as follows: Oxidative processes enhance the reaction of the adaptive response. Oxidation of carbohydrates enhances the anti- The structures of cellular macromolecules and small mol- body response to coadministered coantigens. Moreover, ecules may markedly change by acute or chronic oxidative the administration of the Schiff base-forming agent stress, acting as antigens ("neo-antigens"). Neo-antigens tucaresol during immunization with protein antigen with sufficient homology or identity to host antigenic pro- increased T-cell-dependent immune response. Direct teins induce auto-reactivity. This phenomenon is referred modification of protein antigen has been demonstrated to to as "molecular mimicry" [8,9]. be required for the enhancement of the immune response [9,18]. Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with proteins and make them highly immu- Oxidative stress, which can induce apoptosis by releasing nogenic [10]. Hydroxyl radicals are also very highly reac- caspase activating cytochrome C from mitochondria [19], tive and could attack a wide range of targets. The presence may induce or contribute to apoptosis. Apoptosis is of rheumatoid factors in some autoimmune diseases, such believed to be involved in autoimmunity. During apopto- as vitiligo [9,11] and rheumatoid arthritis, can be sis, modification of cellular antigens through proteolysis, explained by this mechanism. Over time, chronic oxida- changes in the phosphorylation state and citrullination tive stress could generate several adducted and/or non- may give rise to potentially immunostimulatory forms of adducted molecules that would essentially act as a "neo- intracellular or membrane-associated autoantigens. Gen- antigens". This is consistent with the slow maturation of erally, the efficient clearance of apoptotic cells results in auto-antibodies in the evolution of autoimmune diseases. the exposure of intracellular self-antigens to the immune During chronic oxidative stress, neo-antigens potentially system under non-inflammatory conditions, leading to cause tissue damage and release a plethora of sequestered tolerizing of these antigens. It has been proposed that auto-antigens. This process is referred to as the "bystander under these conditions circulating dendritic cell precur- effect". Such an outburst of auto-antigens from the target sors take up apoptotic cells and travel to lymphoid organs, tissue would potentially amplify the effect of the neo-anti- where they present autoantigens from apoptotic cells to T gens, leading to the breakdown of self-tolerance [8]. cells in the absence of costimulatory molecules. However, under a proinflammatory environment, these modified Reactive oxygen species are recognized as important sig- autoantigens, which may also expose cryptic epitopes, nalling molecules within the cells of the immune system. may be processed by mature Langerhans' cells and pre- This is, at least in part, due to the reversible activation of sented to either naïve T cells that have not been tolerized kinases, phosphatases and transcription factors by modi- against the cryptic epitopes or to autoreactive CD4+ and fication of critical thiol residues [9,12]. In fact, free radi- CD8+ that escaped deletion due to defects in T cell apop- cals are involved in specific early events in T cell activation tosis. Subsequently the autoreactive CD4+ T cells may and antioxidants reduce T cell proliferation, IL-2R expres- stimulate autoreactive B cells to produce autoantibodies, sion and IL-2 production [13]. whereas CD8+ T cells may attack cellular antigens directly. It deserves noting that efficient clearance of apoptotic cells It was recently reported that ROS upregulate dendritic cell is crucial for the avoidance of autoimmune responses to surface markers, including MHC Class II molecules, sug- intracellular antigens [9,20]. gesting that antigen-specific, bidirectional dendritic cell-T- cell communication can be blocked by interfering with redox regulation pathways. ROS play a crucial role in acti- Page 3 of 5 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:4 http://www.jautoimdis.com/content/6/1/4 In sum, oxidative stress plays an important role in the eti- i.e. those having fully functional CYP activity, in diverse opathogenesis of the autoimmune diseases by initiating autoimmune diseases. or amplifying the autoimmune response. Implications of the hypothesis If proven, a practical implication of this hypothesis is the Conclusion Given that the metabolism of xenobiotics by CYP leads to prevention of occurrence of autoimmune diseases in pre- the production of ROS, and that ROS contribute crucially disposed individuals or the prevention of relapse of the to the initiation and/or amplification of the autoimmune autoimmune disease in affected individuals by CYP inhib- response, CYP may play a role in the pathobiology of itors. some autoimmune diseases. Abbreviations The author wishes to put more emphasis on the potential CYP: Cytochrome-P-450 enzymes; MAPK: Mitogen-acti- link between CYP polymorphisms and vitiligo, as vitiligo vated protein kinase; NF-κB: Nuclear factor kappa-light- is an autoimmune disorder in which not only ROS but chain-enhancer of activated B cells; ROS: Reactive oxygen also quinones, which could be produced by CYP, are sup- species posed to be crucially involved. It is supposed that reactive quinones can be covalently bound to the catalytic centre Competing interests of tyrosinase to give a neo-antigen. Micro-molar (noncy- The author declares that they have no competing interests. totoxic) quantities of o-quinones may be sufficient in this haptenation to mount an immune response [21]. References 1. Kammer AR, van der Burg SH, Grabscheid B, Hunziker IP, Kwappen- berg KM, Reichen J, Melief CJ, Cerny A: Molecular Mimicry of As mentioned, some cytochrome P450 (CYP) heme-thi- Human Cytochrome P450 by Hepatitis C Virus at the Level olate enzymes participate in the detoxication of xenobiot- of Cytotoxic T Cell Recognition. J Exp Med. 1999, 190(2):169-176. ics. Paradoxically, they can produce reactive intermediates 2. Winqvist O, Gustafsson J, Rorsman F, Karlsson FA, Kämpe O: Two of thousands of chemicals that can damage DNA, as well different cytochrome P450 enzymes are the adrenal anti- gens in autoimmune polyendocrine syndrome type I and as lipids and proteins. CYP expression can also affect the Addison's disease. J Clin Invest. 1993, 92(5):2377-2385. production of molecules derived from arachidonic acid, 3. Yang CH, Smith TJ, Hong J-Y: Cytochrome P-450 Enzymes as and alter various downstream signal-transduction path- Targets for Chemoprevention against Chemical Carcino- genesis and Toxicity: Opportunities and Limitations. Cancer ways. Such changes can be precursors to malignancy. It is Res. 1994, 54(7 Suppl):1982S-1986S. thus believed that CYP could play role in environmental 4. Gonzalez FJ, Tukey RH: Drug metabolism. In Goodman & Gilman's carcinogenesis [22]. Several studies have indicated a link The Pharmacologic Basis of Therapeutics 11th edition. Edited by: Brun- ton LL, Lazo JS, Parker KL. New York: McGraw Hill; 2006:71-91. between rheumatic diseases, autoimmune phenomena, 5. Gonzalez FG, Yu A-M: Cytochrome P450 and xenobiotic recep- and cancers. An increased risk of hematological malignan- tor humanized Mice. Annu Rev Pharmacol Toxicol. 2006, 46:41-64. 6. Bickers DR, Athar M: Oxidative stress in the pathogenesis of cies, compared with the general population, was found skin disease. J Invest Dermatol. 2006, 126(12):2565-2575. among patients with rheumatoid arthritis and systemic 7. Athar M: Oxidative stress and experimental carcinogenesis. lupus erythematosus. Similarly, the prevalence of solid Indian J Exp Biol 2002, 40(6):656-67. 8. Kannan S: Free radical theory of autoimmunity. Theor Biol Med tumours among patients with systemic sclerosis is Model 2006, 3:22. between 3 and 7%. Cancer is also common among der- 9. Namazi MR: Neurogenic dysregulation, oxidative stress, autoimmunity, and melanocytorrhagy in vitiligo: can they be matomyositis patients [23]. It is suggested that the link interconnected? Pigment Cell Res. 2007, 20(5):360-363. between autoimmune phenomena and rheumatic dis- 10. Kurien BT, Hensley K, Bachmann M, Scofield RH: Oxidatively mod- eases may be a result of (a) generation of autoantibodies ified autoantigens in autoimmune diseases. Free Radic Biol Med. 2006, 41(4):549-556. against various autoantigens, (b) paraneoplastic syn- 11. Vahedi Darmian F, Joubeh S, Doroudchi M, Abdollahi B, Ghaderi A: dromes, (c) rheumatism after chemotherapy, a clinical Detection of rheumatoid factors in sera and biopsy lesions of entity characterized by the development of musculoskele- vitiligo patients. Iran J Immunol 2004, 1(1):48-55. 12. Grifiths HR: ROS as signalling molecules in T cells-evidence tal symptoms after combination chemotherapy for malig- for abnormal redox signalling in the autoimmune disease, nancy. I would like to suggest that the involvement of CYP rheumatoid arthritis. Redox Rep. 2005, 10(6):273-280. 13. Chaudhri G, Hunt NH, Clark IA, Ceredig R: Antioxidants inhibit in both carcinogenesis and autoimmunity may prove to proliferation and cell surface expression of receptors for be a hitherto unexplained reason for association between interleukin-2 and transferrin in T lymphocytes stimulated cancer and autoimmunity. with phorbol myristate acetate and ionomycin. Cell Immunol. 1998, 115(1):204-213. 14. Briganti S, Picardo M: Antioxidant activity, lipid peroxidation, Testing the hypothesis and skin diseases. What's new? J Eur Acad Dermatol Venereol. The hypothesis can be tested by comparing the frequency 2003, 17(6):663-669. 15. Matos TJ, Duarte CB, Goncalo M, Lopes MC: Role of oxidative of poor metabolizers, i.e. those with genetically deter- stress in ERK and p38 MAPK activation induced by the mined low or no CYP activity, to extensive metabolizers, chemical sensitizer DNFB in a fetal skindendritic cell line. Immunol Cell Biol. 2005, 83(6):607-614. Page 4 of 5 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:4 http://www.jautoimdis.com/content/6/1/4 16. Chandel NS, Trzyna WC, McClintock DS, Schumacker PT: Role of oxidants in NF-kappa B activation and TNF-alpha gene tran- scription induced by hypoxia and endotoxin. J Immunol. 2000, 165(2):1013-1021. 17. Ahn KS, Aggarwal BB: Transcription factor NF-kappaB: a sen- sor for smoke and stress signals. Ann N Y Acad Sci. 2005, 1056:218-233. 18. Kurien BT, Hensley K, Bachmann M, Scofield RH: Oxidatively mod- ified autoantigens in autoimmune diseases. Free Radic Biol Med 2006, 41(4):549-556. 19. Simon HU, Haj-Yehia A, Levi-Schaffer F: Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 2000, 5(5):415-8. 20. Casiano CA, Pacheco FJ: Cell death and autoimmunity. In Autoantibodies and Autoimmunity Edited by: Pollard KM. Weinheim: Wiley-VCH Verlag; 2006:107-137. 21. Westerhof W, d'Ischia M: Vitiligo puzzle: the pieces fall in place. Pigment Cell Res. 2007, 20(5):345-359. 22. Neber DW, Dalton PT: The role of cytochrome p-450 enzymes in endogenous signaling pathways and environmental car- cinogenesis. Nature Rev Cancer. 2006, 6(12):947-960. 23. Abu-Shakra M, Buskila D, Ehrenfeld M, Conrad K, Shoenfeld Y: Can- cer and autoimmunity: autoimmune and rheumatic features in patients with malignancies. Ann Rheum Dis. 2001, 60(5):433-440. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 5 of 5 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Autoimmune Diseases Springer Journals

Cytochrome-P450 enzymes and autoimmunity: expansion of the relationship and introduction of free radicals as the link

Namazi, MR
Journal of Autoimmune Diseases , Volume 6 (1) – Jun 25, 2009
Download PDF
5 pages

Loading next page...
 
/lp/springer-journals/cytochrome-p450-enzymes-and-autoimmunity-expansion-of-the-relationship-mvp000zJgC

References (24)

Publisher
Springer Journals
Copyright
Copyright © 2009 by Namazi; licensee BioMed Central Ltd.
Subject
Biomedicine; Immunology; Internal Medicine
eISSN
1740-2557
DOI
10.1186/1740-2557-6-4
pmid
19555503
Publisher site
See Article on Publisher Site

Abstract

The Cytochrome-P-450 enzymes (CYP) are among the most important xenobiotic-metabolizing enzymes, which produce reactive oxygen species (ROS) as the result of metabolizing xenobiotics. ROS are believed to play important roles in the pathophysiology of autoimmune diseases. ROS can alter the structure of cellular antigens to produce a "neo-antigen" which could mount an autoimmune response against the original antigen through molecular mimicry. ROS are involved in apoptosis, activation of antigen presenting cells and initiation or amplification of diverse immunologic reactions. Taking all these facts together, it could be speculated that CYP may be involved in the initiation and/or amplification of autoimmune phenomena. "Who is in me, heart-weary, now I know not: the readers to the ability of CYP to induce/amplify autoimmunity through production of free radicals. While I am mute, a voice within me roars..." Presentation of the hypothesis Hafez Shirazi (a great Persian Poet) a) Brief description of CYP enzymes and their involvement in the production of reactive oxygen species (ROS) Background Upon entering the body, a foreign compound is subjected Involvement of cytochrome P450 (CYP) enzymes in the to metabolism by a large group of enzymes, collectively pathogenesis of autoimmune hepatitis type 2, occurring referred as xenobiotic-metabolizing enzymes. Although via molecular mimicry of human cytochrome P450 by originally thought to be responsible for drug metabolism hepatitis C virus at the level of cytotoxic T cell recognition, almost exclusively in the liver, it has now been realized is well appreciated [1]. In addition, two different cyto- that all xenobiotic-metabolizing enzymes participate in chrome P450 enzymes are believed to be the adrenal anti- many crucial endogenous functions, probably in every gens in autoimmune polyendocrine syndrome type I and eukaryotic cell and many prokaryotes. The CYP enzymes Addison's disease [2]. However, except these two diseases are among the most important xenobiotic-metabolizing where CYP serves as the autoantigen and hence functions enzymes and are the products of the CYP superfamily of as the core of the autoimmunity, the potential contribu- genes [3]. They are embedded in the phospholipids tion of CYP in autoimmune diseases has not been investi- bilayer of the endoplasmic reticulum [4]. gated. It is attempted in this paper to draw the attention of Page 1 of 5 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:4 http://www.jautoimdis.com/content/6/1/4 CYPs are named with the root CYP followed by a number olism of bile acids, which are degradation by-products of designating the family, a letter denoting the subfamily, cholesterol. Some CYPs, such as those that catalyze steroid and another number designating the CYP form. Thus, and bile acid synthesis, have very specific substrate prefer- CYP3A4 is family 3, subfamily A, and gene number 4. All ences [4]. CYPs contain a molecule of heme that is noncovalently bound to the polypeptide chain. Metabolism of a sub- The liver contains the greatest abundance of xenobiotic- strate by CYP consumes one molecule of molecular oxy- metabolzing CYPs. More than 50 individual CYP have gen and produces an oxidized substrate plus a molecule of been identified in humans, of which 12 are known to be water as a by-product. However, for most CYPs, depend- important for metabolism of xenobiotics. The expression ing on the nature of the substrate, the reaction is "uncou- of different CYPs can differ markedly through interindi- pled", consuming more O than the metabolized vidual changes resulting from heritable polymorphic dif- substrate and producing activated oxygen or O [4]. CYPs ferences in gene structure. Several human CYP genes metabolize most clinically used drugs and are required for exhibit polymorphisms, including CYP2A6, CYP2C9, metabolic activation of chemical carcinogens and toxins CYP2C19, and CYP2D6 [4]. [5]. Additionally, CYPs are involved in the synthesis of endogenous compounds such as steroids and the metab- Genera Figure 1 tion of ROS by CYP .- Generation of ROS by CYP. Cells generate ROS such as superoxide anion (O ) and H O as a result of metabolism of 2 2 2 .- .- 2+ xenobiotics by CYP. Both O and H O may be converted to the highly reactive hydroxyl radical (OH ) by iron (Fe )-cata- 2 2 2 lyzed Haber-Weiss and Fenton reactions. Many xenobiotics are converted to toxic quinones by CYP. These quinones are .- redox-sensitive agents and are reversibly reduced to semihydroquinones/hydroquinones, which generate O . Page 2 of 5 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:4 http://www.jautoimdis.com/content/6/1/4 Many xenobiotics are converted to toxic quinones by CYP vation of sentinel dendritic cells, linking tissue damage to enzymes (Figure 1). These quinones are redox sensitive initiation of an immune response [9,14]. Addition of agents and are reversibly reduced to semihydoquinones/ DNFB, a strong skin sensitizer, to a dendritic cell line gen- hydroquinone, which generate superoxide anion. Both erated from fetal mouse skin enhanced protein oxidation superoxide anion and hydrogen peroxide may be con- and induced p38 MAPK and extracellular signal-regulated 2+ verted to hydroxyl radical by iron (Fe )-catalyzed Haber- kinase (ERK)1/2 phosphorylation, which could be Weiss and Fenton reactions [6]. Theses reactive molecules blocked by GSH [15]. are more often derived from foreign chemicals (for exam- ple, insecticides) than from endogenous substrates (for Reactive oxygen species activate NF-κB through activation example, lipid peroxides) [7]. of kinases [16]. On activation, NF-κB regulates the expres- sion of almost 400 different genes, which include b)The important role of ROS in the pathogenesis of autoimmunity enzymes such as iNOS, cytokines (such as TNF-α, IL-1 and There are several ways by which ROS could contribute to chemokines), and adhesion molecules [9,17]. the development of autoimmunity. These mechanisms, also discussed fully in reference [9], are as follows: Oxidative processes enhance the reaction of the adaptive response. Oxidation of carbohydrates enhances the anti- The structures of cellular macromolecules and small mol- body response to coadministered coantigens. Moreover, ecules may markedly change by acute or chronic oxidative the administration of the Schiff base-forming agent stress, acting as antigens ("neo-antigens"). Neo-antigens tucaresol during immunization with protein antigen with sufficient homology or identity to host antigenic pro- increased T-cell-dependent immune response. Direct teins induce auto-reactivity. This phenomenon is referred modification of protein antigen has been demonstrated to to as "molecular mimicry" [8,9]. be required for the enhancement of the immune response [9,18]. Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with proteins and make them highly immu- Oxidative stress, which can induce apoptosis by releasing nogenic [10]. Hydroxyl radicals are also very highly reac- caspase activating cytochrome C from mitochondria [19], tive and could attack a wide range of targets. The presence may induce or contribute to apoptosis. Apoptosis is of rheumatoid factors in some autoimmune diseases, such believed to be involved in autoimmunity. During apopto- as vitiligo [9,11] and rheumatoid arthritis, can be sis, modification of cellular antigens through proteolysis, explained by this mechanism. Over time, chronic oxida- changes in the phosphorylation state and citrullination tive stress could generate several adducted and/or non- may give rise to potentially immunostimulatory forms of adducted molecules that would essentially act as a "neo- intracellular or membrane-associated autoantigens. Gen- antigens". This is consistent with the slow maturation of erally, the efficient clearance of apoptotic cells results in auto-antibodies in the evolution of autoimmune diseases. the exposure of intracellular self-antigens to the immune During chronic oxidative stress, neo-antigens potentially system under non-inflammatory conditions, leading to cause tissue damage and release a plethora of sequestered tolerizing of these antigens. It has been proposed that auto-antigens. This process is referred to as the "bystander under these conditions circulating dendritic cell precur- effect". Such an outburst of auto-antigens from the target sors take up apoptotic cells and travel to lymphoid organs, tissue would potentially amplify the effect of the neo-anti- where they present autoantigens from apoptotic cells to T gens, leading to the breakdown of self-tolerance [8]. cells in the absence of costimulatory molecules. However, under a proinflammatory environment, these modified Reactive oxygen species are recognized as important sig- autoantigens, which may also expose cryptic epitopes, nalling molecules within the cells of the immune system. may be processed by mature Langerhans' cells and pre- This is, at least in part, due to the reversible activation of sented to either naïve T cells that have not been tolerized kinases, phosphatases and transcription factors by modi- against the cryptic epitopes or to autoreactive CD4+ and fication of critical thiol residues [9,12]. In fact, free radi- CD8+ that escaped deletion due to defects in T cell apop- cals are involved in specific early events in T cell activation tosis. Subsequently the autoreactive CD4+ T cells may and antioxidants reduce T cell proliferation, IL-2R expres- stimulate autoreactive B cells to produce autoantibodies, sion and IL-2 production [13]. whereas CD8+ T cells may attack cellular antigens directly. It deserves noting that efficient clearance of apoptotic cells It was recently reported that ROS upregulate dendritic cell is crucial for the avoidance of autoimmune responses to surface markers, including MHC Class II molecules, sug- intracellular antigens [9,20]. gesting that antigen-specific, bidirectional dendritic cell-T- cell communication can be blocked by interfering with redox regulation pathways. ROS play a crucial role in acti- Page 3 of 5 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:4 http://www.jautoimdis.com/content/6/1/4 In sum, oxidative stress plays an important role in the eti- i.e. those having fully functional CYP activity, in diverse opathogenesis of the autoimmune diseases by initiating autoimmune diseases. or amplifying the autoimmune response. Implications of the hypothesis If proven, a practical implication of this hypothesis is the Conclusion Given that the metabolism of xenobiotics by CYP leads to prevention of occurrence of autoimmune diseases in pre- the production of ROS, and that ROS contribute crucially disposed individuals or the prevention of relapse of the to the initiation and/or amplification of the autoimmune autoimmune disease in affected individuals by CYP inhib- response, CYP may play a role in the pathobiology of itors. some autoimmune diseases. Abbreviations The author wishes to put more emphasis on the potential CYP: Cytochrome-P-450 enzymes; MAPK: Mitogen-acti- link between CYP polymorphisms and vitiligo, as vitiligo vated protein kinase; NF-κB: Nuclear factor kappa-light- is an autoimmune disorder in which not only ROS but chain-enhancer of activated B cells; ROS: Reactive oxygen also quinones, which could be produced by CYP, are sup- species posed to be crucially involved. It is supposed that reactive quinones can be covalently bound to the catalytic centre Competing interests of tyrosinase to give a neo-antigen. Micro-molar (noncy- The author declares that they have no competing interests. totoxic) quantities of o-quinones may be sufficient in this haptenation to mount an immune response [21]. References 1. Kammer AR, van der Burg SH, Grabscheid B, Hunziker IP, Kwappen- berg KM, Reichen J, Melief CJ, Cerny A: Molecular Mimicry of As mentioned, some cytochrome P450 (CYP) heme-thi- Human Cytochrome P450 by Hepatitis C Virus at the Level olate enzymes participate in the detoxication of xenobiot- of Cytotoxic T Cell Recognition. J Exp Med. 1999, 190(2):169-176. ics. Paradoxically, they can produce reactive intermediates 2. Winqvist O, Gustafsson J, Rorsman F, Karlsson FA, Kämpe O: Two of thousands of chemicals that can damage DNA, as well different cytochrome P450 enzymes are the adrenal anti- gens in autoimmune polyendocrine syndrome type I and as lipids and proteins. CYP expression can also affect the Addison's disease. J Clin Invest. 1993, 92(5):2377-2385. production of molecules derived from arachidonic acid, 3. Yang CH, Smith TJ, Hong J-Y: Cytochrome P-450 Enzymes as and alter various downstream signal-transduction path- Targets for Chemoprevention against Chemical Carcino- genesis and Toxicity: Opportunities and Limitations. Cancer ways. Such changes can be precursors to malignancy. It is Res. 1994, 54(7 Suppl):1982S-1986S. thus believed that CYP could play role in environmental 4. Gonzalez FJ, Tukey RH: Drug metabolism. In Goodman & Gilman's carcinogenesis [22]. Several studies have indicated a link The Pharmacologic Basis of Therapeutics 11th edition. Edited by: Brun- ton LL, Lazo JS, Parker KL. New York: McGraw Hill; 2006:71-91. between rheumatic diseases, autoimmune phenomena, 5. Gonzalez FG, Yu A-M: Cytochrome P450 and xenobiotic recep- and cancers. An increased risk of hematological malignan- tor humanized Mice. Annu Rev Pharmacol Toxicol. 2006, 46:41-64. 6. Bickers DR, Athar M: Oxidative stress in the pathogenesis of cies, compared with the general population, was found skin disease. J Invest Dermatol. 2006, 126(12):2565-2575. among patients with rheumatoid arthritis and systemic 7. Athar M: Oxidative stress and experimental carcinogenesis. lupus erythematosus. Similarly, the prevalence of solid Indian J Exp Biol 2002, 40(6):656-67. 8. Kannan S: Free radical theory of autoimmunity. Theor Biol Med tumours among patients with systemic sclerosis is Model 2006, 3:22. between 3 and 7%. Cancer is also common among der- 9. Namazi MR: Neurogenic dysregulation, oxidative stress, autoimmunity, and melanocytorrhagy in vitiligo: can they be matomyositis patients [23]. It is suggested that the link interconnected? Pigment Cell Res. 2007, 20(5):360-363. between autoimmune phenomena and rheumatic dis- 10. Kurien BT, Hensley K, Bachmann M, Scofield RH: Oxidatively mod- eases may be a result of (a) generation of autoantibodies ified autoantigens in autoimmune diseases. Free Radic Biol Med. 2006, 41(4):549-556. against various autoantigens, (b) paraneoplastic syn- 11. Vahedi Darmian F, Joubeh S, Doroudchi M, Abdollahi B, Ghaderi A: dromes, (c) rheumatism after chemotherapy, a clinical Detection of rheumatoid factors in sera and biopsy lesions of entity characterized by the development of musculoskele- vitiligo patients. Iran J Immunol 2004, 1(1):48-55. 12. Grifiths HR: ROS as signalling molecules in T cells-evidence tal symptoms after combination chemotherapy for malig- for abnormal redox signalling in the autoimmune disease, nancy. I would like to suggest that the involvement of CYP rheumatoid arthritis. Redox Rep. 2005, 10(6):273-280. 13. Chaudhri G, Hunt NH, Clark IA, Ceredig R: Antioxidants inhibit in both carcinogenesis and autoimmunity may prove to proliferation and cell surface expression of receptors for be a hitherto unexplained reason for association between interleukin-2 and transferrin in T lymphocytes stimulated cancer and autoimmunity. with phorbol myristate acetate and ionomycin. Cell Immunol. 1998, 115(1):204-213. 14. Briganti S, Picardo M: Antioxidant activity, lipid peroxidation, Testing the hypothesis and skin diseases. What's new? J Eur Acad Dermatol Venereol. The hypothesis can be tested by comparing the frequency 2003, 17(6):663-669. 15. Matos TJ, Duarte CB, Goncalo M, Lopes MC: Role of oxidative of poor metabolizers, i.e. those with genetically deter- stress in ERK and p38 MAPK activation induced by the mined low or no CYP activity, to extensive metabolizers, chemical sensitizer DNFB in a fetal skindendritic cell line. Immunol Cell Biol. 2005, 83(6):607-614. Page 4 of 5 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:4 http://www.jautoimdis.com/content/6/1/4 16. Chandel NS, Trzyna WC, McClintock DS, Schumacker PT: Role of oxidants in NF-kappa B activation and TNF-alpha gene tran- scription induced by hypoxia and endotoxin. J Immunol. 2000, 165(2):1013-1021. 17. Ahn KS, Aggarwal BB: Transcription factor NF-kappaB: a sen- sor for smoke and stress signals. Ann N Y Acad Sci. 2005, 1056:218-233. 18. Kurien BT, Hensley K, Bachmann M, Scofield RH: Oxidatively mod- ified autoantigens in autoimmune diseases. Free Radic Biol Med 2006, 41(4):549-556. 19. Simon HU, Haj-Yehia A, Levi-Schaffer F: Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 2000, 5(5):415-8. 20. Casiano CA, Pacheco FJ: Cell death and autoimmunity. In Autoantibodies and Autoimmunity Edited by: Pollard KM. Weinheim: Wiley-VCH Verlag; 2006:107-137. 21. Westerhof W, d'Ischia M: Vitiligo puzzle: the pieces fall in place. Pigment Cell Res. 2007, 20(5):345-359. 22. Neber DW, Dalton PT: The role of cytochrome p-450 enzymes in endogenous signaling pathways and environmental car- cinogenesis. Nature Rev Cancer. 2006, 6(12):947-960. 23. Abu-Shakra M, Buskila D, Ehrenfeld M, Conrad K, Shoenfeld Y: Can- cer and autoimmunity: autoimmune and rheumatic features in patients with malignancies. Ann Rheum Dis. 2001, 60(5):433-440. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 5 of 5 (page number not for citation purposes)

Journal

Journal of Autoimmune Diseases – Springer Journals

Published: Jun 25, 2009

There are no references for this article.