Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate "paradoxical" outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of "antioxidant" nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that "paradoxical" roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways.

Oxidative Stress: Noxious but Also Vital

“…Superoxide and H 2 O 2 metabolizing enzymes are generally considered to be the primary antioxidant enzyme defense system in the body [98].…”

“…Natural food-derived components have received great attention in the last 2 decades, and several biological activities showing promising anti-inflammatory, antioxidant, and anti-apoptotic-modulatory potential have been identified. These enzymatic and nonenzymatic antioxidant systems are necessary for sustaining life by maintaining a delicate intracellular redox balance and minimizing undesirable cellular damage caused by ROS [94,97,98]. …”

“…Three types of superoxide dismutases can be encountered in mammalian tissues: copper-zinc containing superoxide dismutase (SOD1) present in the cytosol, manganese containing superoxide dismutase (SOD2) found in the mitochondrial matrix and extracellular superoxide dismutase (SOD3). All three are highly expressed, mainly in the renal tubules of healthy kidneys [15,98,100]. The final product of the SOD activity -H 2 O 2 , is then converted into water and oxygen by the catalase (CAT).…”

“…These enzymes are a family of abundantly present 20-30 kDa peroxidases that are excessively reactive with H 2 O 2 . So, they are likely to be critical for both oxidative stress protection as well as redox signaling [98]. The antioxidant enzymes may possibly offer novel treatment options for redox-related diseases, provided that the molecular mechanisms are known and can be specifically targeted.…”

“…The antioxidant enzymes may possibly offer novel treatment options for redox-related diseases, provided that the molecular mechanisms are known and can be specifically targeted. Besides that, inhibiting a given antioxidant enzyme or specifically silencing its gene expression may help treat disorders related to a gain of enzymatic function [98] and this fact can will help the researchers to explore future options in enzymatic antioxidant system and diseases. …”