28.11: Oxidative stress and DNA integrity (24c.11)
- Page ID
- 117301
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\(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)Oxidative stress is caused by an imbalance between the increased production of multiple reactive oxygen species (ROS) (superoxide, hydrogen peroxide, and hydroxyl radicals) and the decreased protective action of antioxidants that are responsible for the neutralization and removal of ROS. Oxidative stress arising from this imbalance has the potential to damage proteins, deoxyribonucleic acid (DNA), and lipids, and may serve as a potential predictor in the development of different ROS-dependent diseases (e.g.,vascular diseases). Zinc plays an important role in antioxidant defence and the maintenance of cellular DNA integrity. As zinc itself is redox inert, it does not function as an antioxidant per se,instead functioning indirectly as an antioxidant and as a “pro-oxidant” over a limited range of zinc concentrations. Consequently, the term “ pro-antioxidant” is used to describe the indirect functions of zinc as an antioxidant. In contrast, outside this range, zinc is a pro-oxidant. Hence, an increase in cellular oxidative stress and DNA damage may be an early sign of both reductions in cellular zinc as well as zinc overload. For more details see Kloubert and Rink (2015).
Several human studies have investigated whether intracellular DNA strand breaks, assayed using the comet assay, could serve as a functional biomarker of zinc status. In an experimentally-controlled depletion-repletion study in adult men with low intakes of dietary zinc for six weeks (i.e., 0.6mg Zn/d for one week followed by 4mg Zn/d for five weeks), the number of leukocytic DNA strand breaks increased, but declined when dietary zinc intakes were increased to 11mg Zn/d for four weeks (Song et al., 2009). Another study of adult men in which dietary zinc intakes containing 6mg Zn/d (with added phytate) for two weeks were increased to 10mg Zn/d for 4 weeks, also showed improvements in the repair of DNA strand breaks with increased intakes of dietary zinc. Serum protein concentrations associated with the DNA repair process also increased, despite no change in plasma zinc (Zyba et al., 2017). In a field setting in Ethiopia a decrease in DNA strand breaks was observed after supplementing women with 20mg zinc as zinc sulfate or placebo daily for 17 days, again despite no significant changes in plasma zinc.
Taken together, these findings indicate that even modest changes in dietary zinc appear to modulate DNA damage, primarily by reducing cellular oxidative stress, and confirm the sensitivity of the comet assay; see Singh et al. (1988) for assay details. Of note, however, despite modest increases in dietary zinc, there were no measured changes in plasma zinc concentrations, exchangeable zinc pool, erythrocyte or leukocyte zinc concentrations and metallothionein in leukocytes. These findings indicate that zinc attenuates oxidant stress over the range of usual zinc intakes, and in that capacity zinc modulates DNA damage. Nevertheless, many other conditions alter the redox state, so markers of oxidative stress, including DNA strand breaks, are not specific biomarkers for zinc nutrition. Hence, oxidative stress and DNA integrity were classified as “emerging” biomarkers by the BOND Zinc Expert Panel (King et al., 2015).