Handbook of Vitamin C Research

90Figure 1.Ana I. Haza, Almudena García and Paloma MoralesFigure 1. Metabolic activation of N-Nitrosodimethylamine (NDMA) by cytochrome P450 2E1.The number of carbon atoms of the chains bound to the nitroso group of N-Nitrosaminesis one of the determinants of a certain CYP(s) responsible for the activation. Cyclic N-Nitrosamines, such as NPYR and NPIP are primarily activated by CYP2A6. On the otherhand, short chain N-Nitrosamines such as NDMA, are activated by CYP2E1, whereasCYP1A1 is involved in the metabolism of the longer chain N-Nitrosamines, such as NDBA[11]. Although alkylation of DNA is generally assumed to be the primary event in thecarcinogenicity of N-Nitrosamines, additional events are operational to induce DNA damage.It has been sugested that N-Nitrosamines can cause oxidative stress and cellular injury by thegeneration of reactive oxygen species (ROS) [12, 13, 14, 15], as well as nuclear single- anddouble-strand DNA breaks, strand breaks in the mitochondrial DNA and formation of cyclicDNA adducts [16]. Moreover, the DNA of blood leukocytes, including stem cells, may bealkylated by N-Nitrosamine metabolites produced in hepatocytes while the blood circulatesthrough the liver [17].The increasing appreciation of importance of N-Nitrosamines as potential humancarcinogens stimulated intense research on protective dietary factors in chemicalcarcinogenesis. The cytochrome P450 reaction cycle yields, apart from reactive metabolites[18], a variety of ROS (superoxide, hydrogen peroxide and water) [19] which can react withvarious cellular targets. To protect molecules against toxic free radicals and other ROS, cellshave developed antioxidant defences by endogenous enzymatic and/or non-enzymaticcomponents that prevent radical formation, remove radicals before damage can occur, repairoxidative damage, eliminate damage molecules, and prevent mutations [20]. Though an