Free Radical Signaling and Antioxidant Protection

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 6 No. 1 • February 2003

Free Radical Signaling and Antioxidant Protection

Last issue, in our article Why Antioxidants Do Not Necessarily Prevent Aging Due to Free Radicals, we discussed how the generation of free radicals by mitochondria appears to be of much more importance in determining maximum lifespan than tissue antioxidant capacity. In other words, you get more protection from mechanisms that reduce the generation of free radicals in the first place than you do from those that simply sop up the radicals after they have been generated.

This brings us to the topic of this article: preconditioning. Preconditioning is a process in which undergoing a free radical stress at the right time and in the right amount results in a substantial increase in protection against later free radical-initiated damage. Brief periods of heat shock are an example of preconditioning, by upregulating processes that protect against later heat and oxidative stress, and providing cardioprotection. On the other hand, taking a free radical-scavenging supplement at the wrong time can actually reduce or eliminate protection against free radicals that would have occurred otherwise. The reason for these different results is that free radicals are not just bad guys that cause damage. They are important signaling elements in oxidant pathways that change the expression of protective genes and their products.

A new paper1 explains how the protective effects of alcohol are initiated via an oxidant-dependent signaling pathway and how the use of antioxidant supplements at the wrong time can block these protective effects. We have found this paper to be of great practical help in deciding when we drink wine during the day.

The paper starts off by noting that tissues can be preconditioned to resist the deleterious effects (largely free radical-caused) of prolonged ischemia followed by reperfusion (such as occurs during heart attacks and strokes) by short previous exposure to stimuli such as brief periods of vascular occlusion, adenosine, nitric oxide donors, endotoxin derivatives, and oxidants. They note that recent work has shown that consumption of ethanol at low to moderate amounts also causes the inducement of anti-inflammatory preconditioned states that limit both short-term and longer-term ischemia/reperfusion injury. Some of the details of this preconditioning pathway have been discovered, such as the involvement in the protective effects of a single dose on isolated myocytes or intact hearts of protein kinase C-epsilon and ATP-sensitive potassium channels, but not adenosine or oxidants.

Although oxidants seem to play no role in the early phase (one hour after ethanol ingestion in mice) of ethanol preconditioning, they seem to be important signaling elements in the second window of protection (24 hours after ethanol ingestion). Ethanol increases tissue levels of the oxidant-producing enzyme xanthine oxidase. The researchers studied whether this or the oxidant enzyme NAD(P)H oxidase might be the source of the reactive oxygen species that cause the late-phase ethanol preconditioning. In fact, concurrent antioxidant treatment actually completely abolished this late-phase ethanol protection.

The results of these studies showed that oxidants produced as a result of xanthine oxidase and NAD(P)H oxidase that trigger the late ethanol preconditioning are formed during the time frame during which ethanol is elevated in the plasma (i.e., the first 60 minutes after ethanol administration by gavage—stomach tube—in C57BL/6 mice). If antioxidants were given at the same time as alcohol, the effectiveness of late ethanol preconditioning was attenuated, whereas antioxidants given after the first hour following alcohol ingestion had no effect on this later preconditioning. The researchers conclude that the oxidant pathway responsible for this preconditioning occurs during the first hour after alcohol ingestion.

Mice metabolize alcohol much more quickly than humans. Hence, it might be necessary to wait 2 or even 3 hours after drinking alcohol before you take antioxidant supplements in order to get the protective alcohol effects. There was no mouse experiment reported as to when antioxidants could be taken before alcohol ingestion in order to avoid attenuating the alcohol-protective effects. Our guess would be that you should wait about 4 hours after taking antioxidant supplements before drinking alcohol for greatest benefit. For example, Durk takes his allopurinol, a xanthine oxidase inhibitor that protects him from familial gout, at bedtime 3 or 4 hours after drinking wine. Yes, it does require a certain amount of planning when you drink alcohol for best effect.

Resveratrol, a polyphenolic constituent of grapes and, hence, of wine, has also been recently shown to provide pharmacological preconditioning to protect the heart from ischemic-reperfusion injury by upregulating nitric oxide.2


  1. Yamaguchi et al. Late preconditioning by ethanol is initiated via an oxidant-dependent signaling pathway. Free Rad Biol Med 34(3):365-76 (2003).
  2. Hattori et al. Pharmacological preconditioning with resveratrol: role of nitric oxide. Am J Physiol Heart Circ Physiol 282:H1988-95 (2002).

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