THERMAL-DECOMPOSITION OF PHOSPHOLIPID SECONDARY OZONIDES - IMPLICATIONS FOR THE TOXICITY OF INHALED OZONE

While inhalation of ozone is known to cause a variety of health effect s, the reactions at a molecular level that lead to these effects are n ot well understood. One potential path is the reaction of ozone with t he unsaturated fatty acid components of pulmonary surfactant at the ai r-water interface in the lung to form secondary ozonides. These have b een proposed to decompose to free radicals, which can then initiate th e well-known inflammatory response. We report here the first kinetic s tudies of the thermal decomposition of the cis and trans secondary ozo nides of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), a ph ospholipid found in significant quantities in lung surfactant. The ozo nides were synthesized by reaction of O-3 with POPC adsorbed on a glas s surface, and their thermal decomposition kinetics were followed usin g high-performance liquid chromatography (HPLC) over the temperature r ange from 50 degrees C to 106 degrees C in either methanol or 1, 1, 1, 2-tetrachloroethane. The Arrhenius parameters for the thermal decompos ition in methanol are A = 10(8.7+/-0.3) s(-1) and E-a = 19.6 +/- 0.6 k cal mol(-1) for the cis ozonide, and A = 10(8.7+/-0.6) S-1 and E-a = 1 9.8 +/- 1.0 kcal mol(-1) for the trans ozonide. In 1, 1, 1,2-tetrachlo roethane, the parameters are A = 10(8.3+/-2.1) s(-1) and E-a = 18.4 +/ - 3.4 kcal mol(-1) for the cis ozonide, and A = 10(9).(3+/-3.2) s(-1) and E-a = 20.2 +/- 5.2 kcal mol(-1) for the trans ozonide (all errors cited are +/-2 sigma). Within experimental error, there is no differen ce in the kinetics of decomposition in the two solvents. However, both the activation energy and the preexponential factor for the decomposi tion of the phospholipid ozonides are significantly lower than those f or decomposition of the long-chain alkene ozonide 1-octene ozonide, de termined to be E-a, = 26.7 +/- 3.2 kcal mol(-1) and A = 10(12.7+/-1.9) s(-1). The latter reaction has been proposed to be initiated by sciss ion of the O-O bond, followed by decomposition of the peroxy biradical to generate free radicals. The kinetics:for the decomposition of the POPC ozonides in solution are similar to those of simple alkene ozonid es in the gas phase, where a concerted mechanism involving simultaneou s intramolecular hydrogen transfer and O-O bond cleavage has been prop osed. The only high-molecular-weight major product of the POPC ozonide decomposition identified using liquid secondary ion mass spectrometry (LSIMS) was the lipid acid 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosph ocholine which was observed as a product in both solvents. The mechani sm and implications for the toxicology of inhaled ozone are discussed.