Cytochrome-P450 enzymes and autoimmunity: expansion of the relationship and intr

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Cytochrome-P450 enzymes and autoimmunity: expansion of the relationship

and introduction of free radicals as the link

_http://www.jautoimdis.com/content/6/1/4_

(http://www.jautoimdis.com/content/6/1/4)

 

 

MR Namazi

Medicinal and Natural Chemistry Products Research Center and Dermatology

Department, Shiraz University of Medical Sciences, Shiraz, Iran

 

Journal of Autoimmune Diseases 2009, 6:4doi:10.1186/1740-2557-6-4

 

The electronic version of this article is the complete one and can be

found online at: _http://www.jautoimdis.com/content/6/1/4_

(http://www.jautoimdis.com/content/6/1/4)

 

Received: 13 May 2009

Accepted: 25 June 2009

Published: 25 June 2009

 

© 2009 Namazi; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative

Commons Attribution License (_http://creativecommons.org/licenses/by/2.0_

(http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted

use, distribution, and reproduction in any medium, provided the original

work is properly cited.

 

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--------------------------------

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.

----------

---------

 

Hypothesis

 

" Who is in me, heart-weary, now I know not:

 

While I am mute, a voice within me roars... "

 

Hafez Shirazi (a great Persian Poet)

 

----------

-------------

 

Background

 

 

Involvement of cytochrome P450 (CYP) enzymes in the pathogenesis of

autoimmune hepatitis type 2, occurring via molecular mimicry of human

cytochrome

P450 by hepatitis C virus at the level of cytotoxic T cell recognition, is

well appreciated [1]. In addition, two different cytochrome P450 enzymes

are believed to be the adrenal antigens in autoimmune polyendocrine syndrome

type I and Addison's disease [2]. However, except these two diseases where

CYP serves as the autoantigen and hence functions as the core of the

autoimmunity, the potential contribution of CYP in autoimmune diseases has not

been investigated. It is attempted in this paper to draw the attention of the

readers to the ability of CYP to induce/amplify autoimmunity through

production of free radicals.

 

 

Presentation of the hypothesis

 

 

 

 

a) Brief description of CYP enzymes and their involvement in the

production of reactive oxygen species (ROS)

 

Upon entering the body, a foreign compound is subjected to metabolism by a

large group of enzymes, collectively referred as xenobiotic-metabolizing

enzymes. Although originally thought to be responsible for drug metabolism

almost exclusively in the liver, it has now been realized that all

xenobiotic-metabolizing enzymes participate in many crucial endogenous

functions,

probably in every eukaryotic cell and many prokaryotes. The CYP enzymes are

among the most important xenobiotic-metabolizing enzymes and are the

products of the CYP superfamily of genes [3]. They are embedded in the

phospholipids bilayer of the endoplasmic reticulum [4].

 

 

CYPs are named with the root CYP followed by a number designating the

family, a letter denoting the subfamily, and another number designating the CYP

form. Thus, CYP3A4 is family 3, subfamily A, and gene number 4. All CYPs

contain a molecule of heme that is noncovalently bound to the polypeptide

chain. Metabolism of a substrate by CYP consumes one molecule of molecular

oxygen and produces an oxidized substrate plus a molecule of water as a

by-product. However, for most CYPs, depending on the nature of the substrate,

the reaction is " uncoupled " , consuming more O2 than the metabolized substrate

and producing activated oxygen or O2- [4]. CYPs metabolize most clinically

used drugs and are required for metabolic activation of chemical

carcinogens and toxins [5]. Additionally, CYPs are involved in the synthesis of

endogenous compounds such as steroids and the metabolism of bile acids, which

are degradation by-products of cholesterol. Some CYPs, such as those that

catalyze steroid and bile acid synthesis, have very specific substrate

preferences [4].

 

 

The liver contains the greatest abundance of xenobiotic-metabolzing CYPs.

More than 50 individual CYP have been identified in humans, of which 12 are

known to be important for metabolism of xenobiotics. The expression of

different CYPs can differ markedly through interindividual changes resulting

from heritable polymorphic differences in gene structure. Several human CYP

genes exhibit polymorphisms, including CYP2A6, CYP2C9, CYP2C19, and CYP2D6

[4].

 

 

Many xenobiotics are converted to toxic quinones by CYP enzymes (Figure

1). These quinones are redox sensitive agents and are reversibly reduced to

semihydoquinones/hydroquinone, which generate superoxide anion. Both

superoxide anion and hydrogen peroxide may be converted to hydroxyl radical by

iron (Fe2+)-catalyzed Haber-Weiss and Fenton reactions [6]. Theses reactive

molecules are more often derived from foreign chemicals (for example,

insecticides) than from endogenous substrates (for example, lipid peroxides)

[7].

 

 

Figure 1. [ see diagram on webpage]

Generation of ROS by CYP. Cells generate ROS such as superoxide anion

(O2.-) and H2O2 as a result of metabolism of xenobiotics by CYP. Both O2.- and

H2O2 may be converted to the highly reactive hydroxyl radical (OH.-) by

iron (Fe2+)-catalyzed 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 O2.-.

 

 

 

b)The important role of ROS in the pathogenesis of autoimmunity

 

There are several ways by which ROS could contribute to the development of

autoimmunity. These mechanisms, also discussed fully in reference [9], are

as follows:

 

The structures of cellular macromolecules and small molecules may markedly

change by acute or chronic oxidative stress, acting as antigens

( " neo-antigens " ). Neo-antigens with sufficient homology or identity to host

antigenic

proteins induce auto-reactivity. This phenomenon is referred to as

" molecular mimicry " [8,9].

 

Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with

proteins and make them highly immunogenic [10]. Hydroxyl radicals are also

very highly reactive and could attack a wide range of targets. The presence of

rheumatoid factors in some autoimmune diseases, such as vitiligo [9,11]

and rheumatoid arthritis, can be explained by this mechanism. Over time,

chronic oxidative stress could generate several adducted and/or non-adducted

molecules that would essentially act as a " neo-antigens " . This is consistent

with the slow maturation of auto-antibodies in the evolution of autoimmune

diseases. During chronic oxidative stress, neo-antigens potentially cause

tissue damage and release a plethora of sequestered auto-antigens. This

process is referred to as the " bystander effect " . Such an outburst of

auto-antigens from the target tissue would potentially amplify the effect of

the

neo-antigens, leading to the breakdown of self-tolerance [8].

 

Reactive oxygen species are recognized as important signalling molecules

within the cells of the immune system. This is, at least in part, due to the

reversible activation of kinases, phosphatases and transcription factors

by modification of critical thiol residues [9,12]. In fact, free radicals are

involved in specific early events in T cell activation and antioxidants

reduce T cell proliferation, IL-2R expression and IL-2 production [13].

 

It was recently reported that ROS upregulate dendritic cell surface

markers, including MHC Class II molecules, suggesting that antigen-specific,

bidir

ectional dendritic cell-T-cell communication can be blocked by interfering

with redox regulation pathways. ROS play a crucial role in activation of

sentinel dendritic cells, linking tissue damage to initiation of an immune

response [9,14]. Addition of DNFB, a strong skin sensitizer, to a dendritic

cell line generated from fetal mouse skin enhanced protein oxidation and

induced p38 MAPK and extracellular signal-regulated kinase (ERK)1/2

phosphorylation, which could be blocked by GSH [15].

 

Reactive oxygen species activate NF-?B through activation of kinases [16].

On activation, NF-?B regulates the expression of almost 400 different

genes, which include enzymes such as iNOS, cytokines (such as TNF-a, IL-1 and

chemokines), and adhesion molecules [9,17].

 

Oxidative processes enhance the reaction of the adaptive response.

Oxidation of carbohydrates enhances the antibody response to coadministered

coantigens. Moreover, the administration of the Schiff base-forming agent

tucaresol during immunization with protein antigen increased T-cell-dependent

immune response. Direct modification of protein antigen has been demonstrated

to be required for the enhancement of the immune response [9,18].

 

Oxidative stress, which can induce apoptosis by releasing caspase

activating cytochrome C from mitochondria [19], may induce or contribute to

apoptosis. Apoptosis is believed to be involved in autoimmunity. During

apoptosis,

modification of cellular antigens through proteolysis, changes in the

phosphorylation state and citrullination may give rise to potentially immun

ostimulatory forms of intracellular or membrane-associated autoantigens.

Generally, the efficient clearance of apoptotic cells results in the exposure of

intracellular self-antigens to the immune system under non-inflammatory

conditions, leading to tolerizing of these antigens. It has been proposed that

under these conditions circulating dendritic cell precursors take up

apoptotic cells and travel to lymphoid organs, where they present autoantigens

from apoptotic cells to T cells in the absence of costimulatory molecules.

However, under a proinflammatory environment, these modified autoantigens,

which may also expose cryptic epitopes, may be processed by mature

Langerhans' cells and presented to either naïve T cells that have not been

tolerized

against the cryptic epitopes or to autoreactive CD4+ and CD8+ that escaped

deletion due to defects in T cell apoptosis. Subsequently the autoreactive

CD4+ T cells may stimulate autoreactive B cells to produce autoantibodies,

whereas CD8+ T cells may attack cellular antigens directly. It deserves

noting that efficient clearance of apoptotic cells is crucial for the

avoidance of autoimmune responses to intracellular antigens [9,20].

 

In sum, oxidative stress plays an important role in the etiopathogenesis

of the autoimmune diseases by initiating or amplifying the autoimmune

response.

 

 

Conclusion

 

Given that the metabolism of xenobiotics by CYP leads to the production of

ROS, and that ROS contribute crucially to the initiation and/or

amplification of the autoimmune response, CYP may play a role in the

pathobiology of

some autoimmune diseases.

 

The author wishes to put more emphasis on the potential link between CYP

polymorphisms and vitiligo, as vitiligo is an autoimmune disorder in which

not only ROS but also quinones, which could be produced by CYP, are supposed

to be crucially involved. It is supposed that reactive quinones can be

covalently bound to the catalytic centre of tyrosinase to give a neo-antigen.

Micro-molar (noncytotoxic) quantities of o-quinones may be sufficient in

this haptenation to mount an immune response [21].

 

As mentioned, some cytochrome P450 (CYP) heme-thiolate enzymes participate

in the detoxication of xenobiotics. Paradoxically, they can produce

reactive intermediates of thousands of chemicals that can damage DNA, as well as

lipids and proteins. CYP expression can also affect the production of

molecules derived from arachidonic acid, and alter various downstream

signal-transduction pathways. Such changes can be precursors to malignancy. It

is thus

believed that CYP could play role in environmental carcinogenesis [22].

Several studies have indicated a link between rheumatic diseases, autoimmune

phenomena, and cancers. An increased risk of hematological malignancies,

compared with the general population, was found among patients with

rheumatoid arthritis and systemic lupus erythematosus. Similarly, the

prevalence of

solid tumours among patients with systemic sclerosis is between 3 and 7%.

Cancer is also common among dermatomyositis patients [23]. It is suggested

that the link between autoimmune phenomena and rheumatic diseases may be a

result of (a) generation of autoantibodies against various autoantigens, (b)

paraneoplastic syndromes, © rheumatism after chemotherapy, a clinical

entity characterized by the development of musculoskeletal symptoms after

combination chemotherapy for malignancy. I would like to suggest that the

involvement of CYP in both carcinogenesis and autoimmunity may prove to be a

hitherto unexplained reason for association between cancer and autoimmunity.

 

 

Testing the hypothesis

 

The hypothesis can be tested by comparing the frequency of poor

metabolizers, i.e. those with genetically determined low or no CYP activity, to

extensive metabolizers, i.e. those having fully functional CYP activity, in

diverse autoimmune diseases.

 

 

Implications of the hypothesis

 

If proven, a practical implication of this hypothesis is the prevention of

occurrence of autoimmune diseases in predisposed individuals or the

prevention of relapse of the autoimmune disease in affected individuals by CYP

inhibitors.

 

 

Abbreviations

CYP: Cytochrome-P-450 enzymes; MAPK: Mitogen-activated protein kinase;

NF-?B: Nuclear factor kappa-light-chain-enhancer of activated B cells; ROS:

Reactive oxygen species

 

 

Competing interests

The author declares that they have no competing interests.

 

 

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