Valery Menshov and Alexey Trofimov - CORESTA · 10/2/2012 9:37:08 PM Title: Redox processes in a smoker's organism: Between the imbalance and the stress

Redox Processes in a Smoker's Organism: Between the Imbalance and the Stress

Valery Menshov and Alexey Trofimov

Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow

2012 CORESTA CONGRESS

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Is smoking a cause of the oxidative stress?

All the data bases throughout all the time:

> 4000 pubs 99% of conclusions: YES

…But, most frequently, reports are full of: Paradoxes, conflicting data and

contradicting evidence

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…Thus, is smoking indeed a cause of oxidative stress?

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Phenomenology

Terminology

Chronology

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“… Oxidative stress denotes a disturbance in the prooxidant/antioxidant balance in favor of the prooxidants, leading to potential damage …”

H. Sies, Introductory remarks, In: Oxidative Stress, edited by H. Sies, London: Academic Press, 1985, pp. 1–8.

“… An imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage …”

H. Sies, D.P. Jones, Oxidative stress, In: Encyclopedia of Stress (G. Fink, Ed.), 2nd edn., Vol. 3, San Diego, CA: Elsevier, 2007, pp. 45–48.

MORE than 3000 references!!!

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“… In present the role of oxygen radicals and other ROS in the origin or progression of most human diseases remains uncertain…” (B. Halliwell, 2012).

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(1) Cigarette smoke contains ROS, which can get into the bloodstream and cause macromolecular damage in the cells (I. Rahman, 2006):

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(2) Cigarette smoking also elicits a marked activation of leukocytes, which can also contribute to the oxidative lung damage in smokers

Mechanisms of reactive oxygen species (ROS)-mediated lung inflammation: Inflammatory response is mediated by oxidants either inhaled and/or released by the activated neutrophils, alveolar macrophages (AMs), eosinophils (Eos) and epithelial cells leading to production of ROS and membrane lipid peroxidation

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Oxidative stress in everyday’s occurrence:

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The naked mole rat is extraordinarily long-lived for a rodent of its size (up to 28 years). The reason for their longevity is debated, but is thought to be related to their ability to substantially reduce their metabolism during hard times, and so prevent oxidative damage.

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The US National Institute of Health defines a biomarker as “… a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention …”

Biomarkers of the Oxidative Stress

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Biomarkers of the Oxidative Stress and the Redox Imbalance

About 200 of agents and events may serve as potential markers!

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Most Popular Biomarkers of the Oxidative/Nitrosative Stress

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Metabolic Biomarker Smokers`s body Smoke&tobacco

F2-isoprostanes √ ???

Other lipid peroxidation products (MDA, acrolein, LOOH….)

√ √

8-hydroxy-2`-deoxyguanosine (8-OHdG)

√ √

Nitric oxides √ √

Protein carbonyls √ √

Advanced Glycation End products (AGEs) of the Maillard reaction

√ √

H202, O2* √ √

Total Antioxidant Capacity (TAC) √ √

Occurrence of the Pertinent Biomakers in the Smoker’s Body versus that in the Smoke/Tobacco:

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25 35 45 55 656

7

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Female Age, Y

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Japanese Healthy Individuals:

677

Smoking & Nonsmoking

N. Sakano, et al. Oxidative stress biomarkers and lifestyles in Japanese healthy people. J. Clin. Biochem. Nutr. 2009, 44, 185-195.

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What is the threshold between pathological and physiological oxidative stress?

J.D. Morrow, et al. N. Engl. J. Med. 1995, 332, 1198-1203: “... Interestingly, only slightly increased levels of F2-isoprostanes, or none, were found in some of the smokers studied. This finding is of interest in view of the fact that some people appear more resistan than others to the toxic effects o smoking. The reason for this apparent heterogeneity in susceptibility to the oxidative effects of smoking is unclear …”

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Oxidative Stress and Its “Clones” “… Oxidative stress is an ill-defined term

because it cannot be defined by a universal criterion. Instead, different types of oxidative stress exist, each of which can be evaluated by a group of indices that reflect similar reactions …”

(Y. Dotan, et al., 2008)

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MDA production in the control liposome samples (1 mg/ml PC, pH 7.4, 37 oC, curve 1), in the presence of isopropanol portions (30 µl, curve 2) and upon addition of the isopropanol tar extract (2 mg/ml, 30 µl, curve 3).

MDA production in the control liposome samples (1 mg/ml PC, pH 7.4, 37 oC, curve 1) and while exposing the liposome samples to the smoke GP (under the same conditions, curve 2) during the initiated LPO process.

Diverse Effects of the Smoke Phases on the LPO in Liposomes (Our data)

Gas Phase Tar

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Is smoke a source of bioantioxidants? 2012

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Plasma tocopherol dynamics in vitamin-E-supplemented group (15 mg/day, every day, 22 months) (Horwitt, 1956)

Total plasma tocopherol disappearance kinetics (%) in smokers and nonsmokers (Bruno, 2004)

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(T. Nyunoya, et al., 2011)

Intricate Interplay of the Antioxidant Vitamin Supplementation and the Cigarette Smoking

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Antioxidant diet protects against cigarette-smoke-induced emphysema...

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... but potentiates mortality of the experimental animals!

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Antioxidant diet combined with smoking gave a significant gain in the quality of life (preventing the emphysema), but astonishingly reduces the animal’s lifespan! (T. Nyunoya, et al., 2011)

Brief Observation Summary

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Cigarette Smoking, Radiotherapy and Vitamin E Intake (Changes of Hazard Ratio)

RC = recurrence; DA = Death from any cause; DC = death from head & neck cancer;

Sm1: Smoking during a year prior to therapy and no smoking during and after the therapy; Sm2: Smoking during the therapy; Sm3: Smoking during a year following the end of the therapy; (Experimental data from: F. Meyer, et al., Int. J. Cancer. 2008, 122,1679-1683)

… But what was behind the vitamin E intake?

Hazard Ratio (HR): dHR=(HRS-HRNS)/HRNS*100%; HRS (Smokers); HRNS (Nonsmokers)

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Terminology Problems of Oxidative Stress: Is the Devil in the Details?

“... Alternative view on oxidative stress assumes that: (i) oxidative stress occurs through discrete redox pathways within cells, and (ii) oxidative stress involving a disruption of redox circuitry can occur without a global pro-oxidant/anti-oxidant imbalance and molecular damage…”

D.P. Jones: “Redefining oxidative stress”, 2006

? RedOx Imbalance

Oxidative Stress

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CONCLUSIONS • Cigarette smoke is a source of both pro- & antioxidants. Thus, its propensity to trigger the oxidative stress in the smoker’s organism is not straightforward;

• Current terminology used in studying the oxidative stress needs to be revisited, to reach a general agreement on definitions. First of all, the most prominent issue, i.e. that of the “oxidative stress” versus the “redox imbalance”, needs to be finally resolved;

•Choice and validation of biomarkers constitute the major methodological problem in studying the smoking-associated oxidative stress;

•Concerning the current knowledge on the biomedical impact of the cigarette smoking, the major conclusion derived from the our analysis is the following: Although cigarette smoking increases the risks for susceptible to disease people, one cannot state that the oxidative stress is bound to occur in the organisms of healthy smokers.

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Acknowledgment Generous funding by British American Tobacco is gratefully appreciated!

Thank you for your attention!

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Documents

Valery Menshov and Alexey Trofimov - CORESTA · 10/2/2012 9:37:08 PM Title: Redox processes in a smoker's organism: Between the imbalance and the stress