MCS ac Etiology: Redox and CYPs

[michael edward badolato jr]

MCS usually originates from the airway epithelium and its sensory innervation - which has defects due to genetic disposition and environmental exposure.

A defective airway releases excessive inflammation subject to the detox enzyme chemical defense systems concerned with both xenobiotics and endogenous products such as aldehydes resulting from lipid peroxidation and the deactivation of reactive oxygen species (Yang 2008, Bolt 2006, Hayes 2005). It can be imagined they would be suppressed, inhibited, or overwhelmed in an extended chain reaction of oxidative stress (Deluca 2010).

Consumption of oxygen during normal cellular metabolism produces reactive oxygen and nitrogen species (RONS) most inactivated by antioxidant defenses including reduced glutathione, ascorbic acid, alpha tocopheral and enzymes superoxide dismutase, catalase, and glutathione peroxidase (Fisher-Wellman 2010, Datla 2007, Bains 1997, Halliwell 1994).

Balanced formation and inactivation of pro-oxidant species determine intracellular redox environment - represented by the ratios of interconvertable reduced (GSH) to oxidized (GSSG) form of glutathione - responsible for the initiation and regulation of many physiological processes within living systems.

Cellular functions that respond to shift in redox - favoring oxidizing or reducing conditions - include signal transduction, DNA and RNA synthesis, protein synthesis, enzyme activation, and regulation of the cell cycle (Shafer 2001).

A chronic oxidizing shift in redox - involving increased RONS production and decreased antioxidant defense - oxidative stress - has a role in many and varied disease conditions (Chung 2009, Dalle Donne 2006, Halliwell 1994).

 

CHRISTOPOULOS A. & EL-FAKAHANY E. THE GENERATION OF NITRIC OXIDE BY G PROTEIN-COUPLED RECEPTORS. LIFE SC 64;1:1-15 1999:

"...NO...is formed on demand via the actions of NOS (nitric oxide synthase) on L-arginine...

...three distinct dimeric isoforms (Moncada 1997)...

...The form of NOS associated with immunological  or infectious stimuli has been designated inducible NOS (iNOS), as its activation requires induction by cytokines and bacterially-derived lipopolysaccharides (Moncada 1991). Typically, a time lag of approximately 8 hrs is associated between induction of iNOS and detection of NO, in comparison to the extreme rapidity of the activation-response relationship of the constitutive isoforms...the amount of NO produced in the former instance is very high (micromolar range), as required for cytotoxity, whereas the biomodulatory nature of NO, produced via nNOS or eNOS activation, involves the synthesis of low (picomolar) quantities (Moncada 1997)...

...The assignment of the term 'constitutive' to the expression of the nNOS and eNOS isoforms highlights the fact that these enzymes are available for rapid activation in response to the appropriate intracellular signal (e.g. calcium), in contrast to iNOS, where the signal (e.g. cytokines) represents the initial trigger for de novo protein synthesis. However, the fact that nNOS and eNOS exist at a relatively constant expression level does not imply that these levels may not undergo long-term regulation...

...Changes in the regulation of expression of the constitutive isoforms of NOS have more often been associated with a variety of pathophysiological conditions..."

 

HUISMAN A. ET AL. ANTI-INFLAMMATORY EFFECTS OF TETRAHYDROBIOPTERIN (BH4) ON EARLY REJECTION IN RENAL ALLOGRAFTS: MODULATION OF INDUCIBLE NITRIC  OXIDE SYNTHASE. FASEB J 10.1096/FJ01-0890FJE 2002:

"...The NOS enzymes require optimal concentration of the cofactor BH4 and the substrate L-arginine for their function...

...BH4 induces a shift from O2- production by BH4 free iNOS to simultaneous NO and O2- production by BH4 repleted iNOS. When the antioxidant status of the microenvironment is insufficient to prevent the very rapid reaction between O2- and NO... peroxynitrite formation will occur...

...inhibition of iNOS retards the development of vascular injury in models characterized by oxyradical stress (e.g. atherosclerosis and transplantation) whereas in models with intact antioxidant capacity stimulation of iNOS mediates vasculoprotective effects...

...The importance of the endothelial isoform of NO synthase has been well established. Endothelium-derived NO has been shown to be essential for vascular homeostasis...

...Classically, iNOS has been regarded as an enzyme that produces nanomolar amounts of the NO radical, thereby causing cellular damage. The current study shows that iNOS can be a O2-, peroxynitrite as well as an NO-producing enzyme. The biological effects of iNOS not only depend on which radical species is released by the enzyme, but also on the antioxidant capacity of the cellular microenvironment of the enzyme..."

 

KHATSENKO O. ET AL. NITRIC OXIDE IS A MEDIATOR OF THE DECREASE IN CYTOCHROME  P450-DEPENDENT METABOLISM CAUSED BY IMMUNOSTIMULANTS. PROC N ACAD SC USA 90:11147-51 1993:

"...(i) LPS (bacterial lipopolysaccharides) induces the release of intermediary cytokines, which, in turn, induce NOS activity in Kupffer cells and hepatocytes;(ii) NO binds to heme iron in cytochromes P450 and prevents oxygen binding, thereby blocking enzyme activity; (iii) NO may also enhance degradation of cytochromes P450 by nitrosylation of heme or thiols in P450 apoprotein or impair transcriptional activation of P450...

...In summary, cytokine induced overproduction of NO could explain attenuation of activity, content, and transcription of cytochromes P450 by a diverse array of immunostimulants..."

 

DELUCA C. ET AL BIOLOGICAL DEFINITION OF MULTIPLE CHEMICAL SENSITIVITY FROM REDOX STATE AND CYTOKINE PROFILING AND NOT FROM POLYMORPHISMS OF XENOBIOTIC-METABOLIZING ENZYMES. TOX AND APPLIED PHARM 248;285-92 2010 :

"...the ubiquitous chemical defense network (phase I-II xenobiotic metabolizing and antioxidant enzymes) appears very early in the evolution and handles low molecular weight inorganic and organic xenobiotics, as well as endogenous non-protein signaling molecules, mediators of inflammation, degradation products, and toxic products of cellular metabolism (Goldstone 2006)..."

 

Phase I reactions form a new or modified functional group or a cleavage (oxidation, reduction, hydrolysis). These are non synthetic - the most important are cytochrome P450 isoenzymes (CYPs) that transfer electrons and catalyze oxidation.

Phase II reactions are synthetic - involving conjugation with an endogenous compound forming metabolites more polar and readily excreted by the kidneys and liver in urine and bile (Merck 1999).

Phase I and II enzymes apply to organic compounds including hydrocarbons of the ambient combustion aerosol.

A genetic finding among metabolizing enzymes is not necessary since the factor specific to MCS is the genetic propensity of sensory irritant receptors - their peptidenergic transmission - greater inflammatory release - furthering local tissue damage and setting forth the systemic reaction of oxidative stress.

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