Photo-oxidation of lipids by singlet oxygen: a theoretical study Ismael Tejero a , Angels Gonza ´lez-Lafont a , Jose ´ M. Lluch a , Leif A. Eriksson b,c, * a Departament de Quı ´mica, Universitat Auto ` noma de Barcelona, 08193 Bellaterra, Barcelona, Spain b Department of Natural Sciences, O ¨ rebro University, Fakultetsgatan 1, 701 82 O ¨ rebro, Sweden c Department of Cell and Molecular Biology, Box 596, Uppsala University, 751 24 Uppsala, Sweden Received 8 September 2004; in final form 8 September 2004 Available online 7 October 2004 Abstract The photo-oxidation reactions between lipid model nona-3,6(c,c)-diene and singlet molecular oxygen are investigated using den- sity functional theory and polarized continuum models. Additions to both the 3- and 4-position of the lipid model (corresponding to the 9(13)- and 10(12)-positions of 9,12 lipid dienes such as linoleic acid) are explored. It is concluded that the modes of attack will lead to adduct intermediates which evolve either to dioxetane formation overcoming a significant energy barrier, or to the final LOOH products (hydro-peroxide bonded to either the 3- or 4-position), for which no transition barriers towards H-abstraction could be located. The computed energy surfaces are in close accord with results for the reactions between singlet oxygen and other unsaturated systems, and explain both the observed difference in product distribution in biological samples and, through the high energy barriers to addition of the initial reactants (15–20 kcal/mol), the low reactivity of singlet oxygen in biological membranes. Ó 2004 Elsevier B.V. All rights reserved. 1. Introduction Lipid peroxidation reactions are essential compo- nents in many pathobiological processes such as athero- sclerosis, carcinogenesis or cell death, and are initiated by the generation of reactive oxygen species (ROS) in the vicinity of the lipid in question [1]. The peroxidations initiate chain reactions leading to the decomposition of phospholipids, or addition reactions (polymerizations) of lipid oxides or fragments thereof. While the former lead to the formation of several toxic by-products, the latter lead to reduced fluidity of the membranes which has implications for membrane transport and cell signal- ling, and has also been discussed in the development of AlzheimerÕs disease [2]. Development of atherosclerosis is known to result from oxidatively damaged low-den- sity lipoproteins (LDL) and subsequent uptake of these by macrophages, leading to the formation of Ôfoam cellsÕ [3–8]. The peroxidation reactions may be divided into three classes: auto-oxidation, photo-oxidation and enzymatic oxidation [1,9]. In the auto-oxidation reactions, an oxy- gen free radical (HO Å ; HOO Å ; O ÅÀ 2 , and similar) is gener- ated radiolytically, through Fenton chemistry, or through leakage in the normal respiration processes in the cells. The oxygen radicals, and in particular the hyd- roxyl radical, will readily abstract a hydrogen atom from the hydrocarbon chain, leading to a radical site in the lipid and subsequent radical driven polymeriza- tion. In addition, molecular oxygen or other species may add to the radical site, thereby providing a wealth of possible reaction pathways. The second class, photo-oxidation, involves the phot- odynamic generation of singlet oxygen ( 1 D g state) via a sensitizer, and the addition of this to an unsaturated bond in the fatty acid. Hydrogen atom transfer from a neighbouring –CH 2 – group to the terminal oxygen leads to the formation of hydroperoxy lipids, LOOH, that in turn can undergo decomposition reactions. Several nat- ural photosensitizers such as tetrapyrroles (bilirubin), flavins, chlorophyll, hemoproteins and reduced pyridine 0009-2614/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.cplett.2004.09.093 * Corresponding author. E-mail address: leif.eriksson@nat.oru.se (L.A. Eriksson). www.elsevier.com/locate/cplett Chemical Physics Letters 398 (2004) 336–342