CHAPTER 16 The Role of Antioxidants in the Prevention of Oxidative Damage to Nucleic Acids Peter Meller and Steffen Loft Abstract I t is commonly assumed that ingestion of antioxidants is associated with low levels of oxidatively damaged DNA although this is far from conclusive in human intervention trials. A collective interpretation is difficult because many studies lack sufficient control and have unrealistically high baseline levels of oxidative DNA damage in human white blood cells (WBC). A survey of studies on the antioxidant hypothesis in terms of oxidative DNA damage excretion products in urine indicates that ingestion of antioxidant-rich foods may be more effective than single antioxidants. In WBC, there is some evidence of beneficial effects of ingestion of antioxidants and antioxidant-rich foods. This suggests intake of antioxidants ei- ther in tablet form or as natural ingredients of foods are associated with beneficial effects on oxidative stress status, but the effect is smaller than previously expected and supplementation of antioxidants to healthy and sufficiently nourished individuals may not be of large public health relevance. Introduction The role of antioxidants in the prevention of DNA oxidation can be investigated in a wide array of experimental settings, ranging from cell free systems, to large intervention studies. 'Antioxidant' is a widely used term that is difficult to define clearly in biological systems and the effect may depend on the experimental setting. We use the term antioxidant as a broad definition of any substance that can prevent oxidation ofbiomolecules, either directly by scav- enging ROS, or indirectly by upregulating the antioxidant defense or DNA repair systems. The indirect antioxidant effect may be induced by xenobiotics or components in vegetables that are not scavengers or even considered potentially harmful e.g., isothiocyanates from cruciferous vegetables. The types of antioxidants can roughly be grouped into categories in relation to administration, as follows: (1) single antioxidants; (2) multiple antioxidants; (3) extracts or juices of natural food products. Antioxidants like vitamin C, vitamin E, carotenoids, and fla- vonoids have been identified in a large range of natural food products, I but fruit and vegetables also contain a mixture of other antioxidants and bioreactive substances that are less well inves- tigated in terms of antioxidant properties. Cell free systems and cell cultures exposed to a ROS generating system are commonly used to investigate the scavenging effect of dietary compounds. The large number of investigations addressing the in vitro antioxidant potential of phytochernicals by far impedes a thorough ·Corresponding Author: Peter Moller-Institute of Public Health, University of Copenhagen, Building B, 2nd FI., 0ster Farimagsgade 5, Post Box 2099, DK-l 014 Copenhagen K, Denmark. Email: p.moller@pubhealth.ku.dk Oxidative Damage to Nucleic Acids, edited by Mark D. Evans and Marcus S. Cooke. ©2007 Landes Bioscience and Springer Science-Business Media.