Biomed & Pharmacother 1999 ; 53 : 169-80 0 Elsevier, Paris Dossier: Oxidation and antioxidizing agents Oxidative stress induced in pathologies: the role of antioxidants L. Gat&, J. Paul’, G. Nguyen Bal, K.D. Tew*, H. Tapierol 1 Luboratoire de Phartnacologie Cellulaire et Moleculaire, UMR CNRS 8612, Universite’ de Paris XI - Facultk de Phartnacie, 92290 Chcftenay-Malabry, France: 2 Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 191 II, USA Summary-Exposure to oxidant molecules issued from the environment (pollution, radiation), nutrition, or pathologies can generate reac- tive oxygen species (ROS for example, H,O,, O,-, OH). These free radicals can alter DNA, proteins and/or membrane phospholipids. Deple- tion of intracellular antioxidants in acute oxidative stress or in various diseases increases intracellular ROS accumulation. This in turn is responsible for several chronic pathologies including cancer, neurodegenerative or cardiovascular pathologies. Thus, to prevent against cellular damages associated with oxidative stress it is important to balance the ratio of antioxidants to oxidants by supplementation or by cell induction of antioxidants. 0 1999 Elsevier, Paris aging I antioxidants I diseases / free radicals The generation of free radicals in vivo is a constant phe- nomenon due either to physiological metabolism or pathological alterations. Oxygen (0,) plays a double role in the cell: it is essential for aerobic organisms, but it can also act as a free radical since it contains two relatively stable unpaired electrons. When an oxygen molecule captures an electron it becomes a superoxide anion O,m. This molecule is normally produced by macrophages in order to destroy bacteria during the pro- cess of phagocytosis. However, this species can also be generated during oxidative phosphorylation in the res- piratory chain in mitochondria. 0, can also be gener- ated in a dismutation reaction by the action of superox- ide dismutase (SOD) to form hydrogen peroxide H,O, (figure I). Furthermore, H,Oz can also be generated from O,- by the radical-generating enzymes amino acid oxidase and xanthine oxidase. Hydrogen peroxide, although less reactive than 0, is more highly diffusible and can cross the plasma mem- brane. One of the physiological functions of H,O, is the activation of nuclear translocation of the transcription factor NFkB, which subsequently allows the transcrip- tion of specific genes. NFkB is a heterodimer of p65 and ~50, but it is only the ~65 subunit that has transcrip- tional activity [ 11. In normal conditions, ~65 is associ- ated with an inhibitory subunit IkB [2], which prevents the translocation of NFC into the nucleus. Although it has been shown that ~65 can be activated by several stimuli including TNFa, IL- 1, phorbol 12-myristate- 13-acetate (PMA), or H,O, [3], the action of protein kinase C (PKC) seems to play the crucial role in the acti- vation of ~65 [4, 51. The H,O,-induced activation of NFkB is achieved via OH production [6]. The nuclear translocation of NFkB after activation by H202 induces the transcription of the HIV proteins and the replication of the virus [7], thus enhancing the pathogenicity of HIV. By homolytic fission, a hydroxyl radical OH can be produced from H202 (the Fenton reaction), this reac- tion being catalyzed by transition elements such as Fe*+. OH can also be generated from O,- or from H,O, and trace elements (the Haber-Weiss reaction). OH is the most highly reactive oxidant molecule, it binds and oxidizes DNA, lipids and proteins, and it reacts with structures from its close neighborhood [8]. Thus oxidants can modulate the generation of second messengers such as diacyglycerol or phosphatidic acid (PA). This latter is generated by phospholipase D (PLD) and PKC activation. PA has mitogenic properties increasing DNA synthesis and cell proliferation in smooth muscle cells [9], and this proliferation may be important in the formation of atherosclerotic plaques [lo]. Moreover, oxidized low-density lipoproteins (LDL) when acting as an activator of PLD, can induce proliferation of smooth muscle cells [ 111, and it may in part be responsible for arteriosclerosis. Thus, by their deleterious effects on macromolecules, oxidants can induce cellular alterations which can lead to the devel-